A pharmaceutical composition comprising rivaroxaban particles with improved bioavailability

Abstract

According to the present invention, by selecting an appropriate range of rivaroxaban particle size and hydrophilic polymer content, it is possible to provide a rivaroxaban composition having bioavailability independent of food while using microscale rivaroxaban particles.

Description

A PHARMACEUTICAL COMPOSITION COMPRISING RIVAROXABAN PARTICLES WITH IMPROVED BIOAVAILABILITY

[0001] The present invention relates to a pharmaceutical composition using rivaroxaban particles.

[0002] Rivaroxaban is a selective, direct factor Xa inhibitor that serves as an anticoagulant by inhibiting factor Xa, which promotes thrombin synthesis. The anticoagulant action of rivaroxaban reduces the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation, treats deep vein thrombosis and pulmonary embolism, and reduces the risk of recurrent deep vein thrombosis and pulmonary embolism.

[0003] Rivaroxaban is a poorly soluble substance corresponding to Biopharmaceutics Classification System (BCS) Class 2 and has a very low solubility in water of approximately 7 mg / L. Therefore, its bioavailability varies greatly depending on whether the patient has eaten food, and there is a problem that its bioavailability decreases when taken before meals. To solve this problem, a method of preparing rivaroxaban through wet granulation (Korean Patent Publication No. 10-1151117, Patent Document 1) was attempted, but the Xarelto tablet, the commercially available rivaroxaban formulation produced by applying this technology, has failed to achieve sufficient bioavailability, and thus the 20 mg tablet must be administered with food.

[0004] A method of melting rivaroxaban into an amorphous state and preparing it into a solid dispersion (Korean Patent Publication No. 10-2362787, Patent Document 2) was attempted. However, since the amorphous state is unstable and tends to change into a stable crystalline state during storage, there is a problem that bioavailability may decrease during storage, and therefore, the method was not sufficient to solve the above problem.

[0005] There are methods to improve solubility, such as a hot melt granulation method (EU Patent Publication No. 2,266,541, Patent Document 3) where rivaroxaban and additives are heated at high temperature, a solubilization method by controlling the solid particle size of the rivaroxaban drug and adsorbing a solubilizer on the surface of the drug (Korean Patent Publication No. 10-2016-0098508, Patent Document 4), a method of increasing water solubility by complexing rivaroxaban with lactose and hydroxypropyl methylcellulose (HPMC) (Korean Patent Publication No. 10-2333463), and a solubilization method through wet granulation of a hydrophilic graft copolymer and rivaroxaban (Korean Patent Publication No. 10-2271862). However, these methods did not achieve an improvement in bioavailability sufficient to enable administration regardless of food.

[0006] The hot melt granulation method has a problem that the crystal form of rivaroxaban changes to an amorphous form, which reduces bioavailability during storage. Although controlling the solid particle size and using a solubilizer are good for increasing solubility, there is a limit to solubilization because the solubilizer may be toxic when used in excess and therefore, its use is limited. The solubility of rivaroxaban may improvein vitrowhen combined with a hydrophilic polymer. However, due to the polymeric properties, when it is used in excess, the viscosity increases, making manufacturing difficult, and dissolution may be delayed, which may rather reduce bioavailabilityin vivoor have a minimal effect. When the particles are pulverized to a nano-size, a large increase in bioavailability may be expected, but there is a concern that the main ingredient may dissolve during the process due to the high energy required for pulverization, which may change the crystal form, and the particles may easily re-agglomerate, resulting in reduction of bioavailability during manufacturing or storage. In addition, rivaroxaban products that are affected by diet use microscale micronized rivaroxaban, so there is a problem that it is difficult to expect an improvement in bioavailability sufficient to ensure the absence of dietary effects simply by reducing the particle size.

[0007] [Related Art Documents]

[0008] [Patent Documents]

[0009] (Patent Document 1) Korean Patent Publication No. 10-1151117

[0010] (Patent Document 2) Korean Patent Publication No. 10-2362787

[0011] (Patent Document 3) EU Patent Publication No. 2,266,541

[0012] (Patent Document 4) Korean Patent Publication No. 10-2016-0098508

[0013] (Patent Document 5) Korean Patent Publication No. 10-2333463

[0014] (Patent Document 6) Korean Patent Publication No. 10-2271862

[0015] In order to solve the above-described problems of the related art, the present invention provides: micronized rivaroxaban particles for preparing an oral pharmaceutical composition, having a microscale particle size, excellent bioavailability, and a minimized drug absorption variation in the gastrointestinal tract; a pharmaceutical composition including the same; and a method of preparing the same.

[0016] Attempts have been made to increase the bioavailability of poorly soluble drugs and minimize the drug absorption variation in the gastrointestinal tract, but a decrease in the particle size of poorly soluble drugs does not always correlate with an increase in bioavailability.

[0017] The commercially available Xarelto tablet (20 mg) uses rivaroxaban particles prepared through wet granulation, as disclosed in International Patent Publication WO 2005 / 060940. However, the rivaroxaban particles did not achieve sufficient bioavailability, so the 20 mg tablet had to be administered with food. A method of melting rivaroxaban to make an amorphous solid dispersion was devised, but the amorphous form is unstable and tends to change into a stable crystalline form during storage, and thus bioavailability may decrease during storage. In addition, there are methods such as solubilization using a hot melt granulation method, a solubilization method by controlling the solid particle size of the rivaroxaban drug and adsorbing a solubilizer on the surface of the drug, a method of increasing the water solubility by complexing rivaroxaban with lactose and hydroxypropyl methylcellulose (HPMC), and a solubilization method through wet granulation of a hydrophilic graft copolymer and rivaroxaban, but they did not achieve an improvement in bioavailability enough to enable administration regardless of food.

[0018] Accordingly, the present inventors have tried to prepare rivaroxaban particles having a microscale particle size (μm), excellent bioavailability, and a minimized drug absorption variation in the gastrointestinal tract.

[0019] As a result, the present inventors have confirmed that selecting an appropriate rivaroxaban particle size and simultaneously using an appropriate amount of hydrophilic polymer is critical in achieving a high dissolution rate and high bioavailability of rivaroxaban.

[0020] In Experimental Example 1 of the present invention, through an experiment on the change in the dissolution rate according to the particle size, it was found that Examples 1 and 2 where the d(50) of the rivaroxaban particle size was 3 μm or less exhibited a dissolution rate of 55% or more in 45 minutes, showing a higher dissolution rate than that of the Xarelto tablet.

[0021] In Experimental Example 2 of the present invention, the dissolution rates of Examples 3 and 4, which were prepared as dispersions using a high-pressure dispersion process, and that of Example 5, which was prepared as a dispersion without using a high-pressure dispersion process, were compared. Example 5, which was not subjected to a high-pressure dispersion process, showed a low dissolution rate of 40% or less, but Examples 3 and 4, which were prepared by a high-pressure dispersion process and in which the d(50) of the rivaroxaban particle size was 3 μm or less, showed a dissolution rate of 55% or more in 45 minutes. Through this, it was confirmed that the dissolution rate of Examples 3 and 4 was higher than that of the Xarelto tablet.

[0022] In Experimental Example 3, Examples 6 to 8 in which the d(50) of the rivaroxaban particle size was 3 μm or less and the content of each hydrophilic polymer was different were prepared. The 45-minute dissolution rate of Examples 6 to 8 was about 70% to 80%.

[0023] Therefore, it was determined that even when the d(50) of the rivaroxaban particle size was 3 μm or less, there was a difference in the dissolution rate depending on the presence / absence of the high-pressure dispersion process and the content of the hydrophilic polymer.

[0024] In Experimental Example 4, the tablet of Example 7 and the Xarelto tablet were compared in a fasted state simulated intestinal fluid and a fed state simulated intestinal fluid, and it was confirmed that Example 7 exhibited a high dissolution rate regardless of the fasted / fed state and that the dissolution rate was improved compared to the Xarelto tablet.

[0025] In Experimental Example 5, it was confirmed that the preprandial / postprandial bioavailability of the pharmaceutical composition containing the micronized rivaroxaban according to the present invention was equivalent.

[0026] Therefore, the present invention provides a pharmaceutical composition including micronized rivaroxaban, a pharmaceutically acceptable salt thereof, and a hydrophilic polymer, wherein particles of the micronized rivaroxaban have a d(50) value of 3 μm or less.

[0027] In the present invention, the particles of the micronized rivaroxaban may have a d(50) value of 3 μm or less, for example, 3 μm or less, for example, 2.8 μm or less, 2.6 μm or less, 2.4 μm or less, 2.2 μm or less, 2.0 μm or less, 1.8 μm or less, 1.6 μm or less, 1.4 μm or less, 1.2 μm or less, 0.8 μm or less, 0.6 μm or less, 0.4 μm or less, or 0.2 μm or less, but are not limited thereto.

[0028] In the present invention, the particles of the micronized rivaroxaban may have a d(90) value of 6 μm or less, but are not limited thereto.

[0029] As described above, the rivaroxaban particles used in the pharmaceutical composition of the present invention preferably have a d(90) value of 6 μm or less because a problem may occur in the stability of the main ingredient when the size of the rivaroxaban particles is reduced to a nanometer level. The rivaroxaban particles may have a d(90) value of 3 to 6 μm, but are not limited thereto. For example, the rivaroxaban particles may have a d(90) value of 3.3 to 5.0 μm.

[0030] Although not specified with a specific example, the pharmaceutical composition desired in the present invention may be obtained by using rivaroxaban particles having d(50), d(90), and / or average particle size values within the ranges exemplified above.

[0031] Methods of micronizing drug particles are well known in the art. For example, a conventional mill capable of micronizing particles, such as a Z-mill, a hammer mill, a ball mill, or a fluid energy mill, may be used for pulverization. In addition, a size classification method, such as a sieving method performed using a sieve or an air current classification method, may be used to refine the drug particle size. Methods of controlling particles to a desired size are well known in the art. For example, see the following literature: [Pharmaceutical Dosage Forms: Volume 2, 2nd Edition, Ed.: H. A. Lieberman, L. Lachman, J. B. Schwartz (Chapter 3: SIZE REDUCTION)].

[0032] Herein, the drug particle size is also expressed based on a particle size distribution such as d(X) = Y (wherein X and Y are positive numbers). The expression, d(X) = Y, means that when the drug particle size distribution obtained by measuring the particle diameter of a certain drug within a formulation is expressed in a cumulative curve, the particle diameter at the point where the particle sizes are accumulated from the smallest in an increasing order and reach X% (the percentage is calculated based on number, volume, or weight) is Y. For example, d(10) represents the particle diameter at the point where the particle sizes of the drugs are accumulated in order of smallness and becomes 10%, d(50) represents the particle diameter at the point where the drug particle sizes are accumulated from the smallest in an increasing order and reach 50%, and d(90) represents the particle diameter at the point where the drug particle sizes are accumulated from the smallest in an increasing order and reach 90%.

[0033] Herein, d(X) is also expressed as d(0.X), and d(X) and d(0.X) may be used interchangeably. For example, d(50) is also expressed as d(0.5), and d(10) and d(90) are also expressed as d(0.1) and d(0.9), respectively.

[0034] Whether the particle size distribution d(X) represents a percentage of the total cumulative particles by number, volume, or weight depends on the method used to measure the particle size distribution. Methods of measuring particle size distributions and the types of percentage associated with them are well known in the art. For example, when a particle size distribution is measured by the well-known laser diffraction method, the X value of d(X) represents a percentage calculated by a volumetric average. It is well known to those skilled in the art that particle size distribution measurement results obtained by a particular method may be correlated with those obtained by other techniques based on experience by common experimentation. For example, the laser diffraction method is sensitive to particle volume and provides a volume-average particle size, which corresponds to a weight-average particle size when the density is constant.

[0035] In the present invention, the average particle size and particle size distribution of rivaroxaban particles may be measured using a commercially available instrument based on the laser diffraction / scattering method based on the Mie theory. For example, measurement is performed using a commercially available device such as the Mastersizer laser diffraction instrument from Malvern Instruments. This instrument irradiates particles with a helium-neon laser beam and the blue light of a blue light-emitting diode to cause scattering, and a light scattering pattern appears on a detector. This light scattering pattern is interpreted according to the Mie theory to obtain the particle diameter distribution. The measurement method can be either a dry method or a wet method, but in the examples below, the results measured using a wet method are shown.

[0036] In the pharmaceutical composition of the present invention, a hydrophilic polymer is necessarily used to stabilize micronized rivaroxaban.

[0037] In the present invention, the hydrophilic polymer not only helps the pulverization of rivaroxaban and the redispersion of micronized rivaroxaban, but also serves as a solubilizer that improves the dissolution rate of rivaroxaban.

[0038] In the present invention, the hydrophilic polymer may be one or more selected from the group consisting of hypromellose, povidone, copovidone, polyvinylpyrrolidone, polyethylene glycol, a copolymer of vinylpyrrolidone-vinylacetate, hydroxypropyl cellulose, hydroxyethyl cellulose, polyvinyl alcohol, and a methacrylate copolymer.

[0039] In the present invention, the hydrophilic polymer may be a copolymer of hypromellose, povidone, or copovidone, but is not limited thereto. In one embodiment of the present invention, the hydrophilic polymer may be one or more selected from the group consisting of hypromellose, povidone, and copovidone.

[0040] In the present invention, the hydrophilic polymer may be included in an amount of 0.25 to 0.8 parts by weight based on 1 part by weight of the micronized rivaroxaban, but is not limited thereto.

[0041] In the present invention, the pharmaceutical composition may further include a surfactant.

[0042] The surfactant serves to suppress the aggregation of micronized rivaroxaban and help its redispersion. Increasing the content of surfactant is good in terms of increasing the redispersion rate of micronized rivaroxaban or rivaroxaban pulverized into a nano-size, but since an increased content of surfactant may be harmful to the human body, it is better to use a small amount of surfactant.

[0043] In the present invention, the surfactant may one or more selected from the group consisting of poloxamer, sodium lauryl sulfate, a docusate salt, sucrose, a stearate salt, a cetyltrimethylammonium salt, fatty alcohol ethoxylate, glycerol monostearate, glycerol monolaurate, sorbitan monolaurate, sorbitan monostearate, sorbitan monooleate, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monostearate, and polyoxyethylene monooleate, but is not limited thereto.

[0044] In one embodiment of the present invention, the surfactant may be poloxamer and sodium lauryl sulfate.

[0045] In the present invention, the surfactant may be included in an amount of 0.05 to 0.15 parts by weight per 1 part by weight of rivaroxaban. Since the surfactant content is significantly reduced compared to previously reported rivaroxaban compositions, it provides an advantage in terms of human safety.

[0046] In the present invention, the pharmaceutical composition may exhibit bioequivalence when administered to a person in a fed state compared to administration to a person in a fasting state, and the bioequivalence may satisfy conditions:

[0047] (i) Cmaxis within log 0.8 to log 1.25 at a 90% confidence interval, and

[0048] (ii) an area under curve (AUC) is within log 0.8 to log 1.25 at a 90% confidence interval.

[0049] In addition, the present invention provides a pharmaceutical composition, wherein the preprandial / postprandial bioavailability of rivaroxaban in the pharmaceutical composition is at a bioequivalent level in terms of area under the blood concentration-time curve (AUC) and peak blood concentration (Cmax). In one embodiment, the present invention provides a pharmaceutical composition, wherein the preprandial / postprandial bioavailability of rivaroxaban in the pharmaceutical composition is at a bioequivalent level in terms of AUC and Cmax.

[0050] Here, whether the AUC and the Cmaxshow a bioequivalence level may be determined according to the pharmaceutical equivalence criteria. For example, when the AUC and the Cmaxof the reference drug and the test drug are log-transformed and statistically processed according to the bioequivalence test of the Pharmaceutical Equivalence Test Standards of the Collection of Pharmaceutical Affairs Laws and Regulations, when both items satisfy the condition that the difference in the log-transformed means is within log 0.8 to log 1.25 at a 90% confidence interval, the test drug is considered equivalent in the pharmaceutical equivalence test. However, as a bioequivalence exception provision, equivalence is determined when both of the following conditions are satisfied: 1) the difference in the log-transformed means of the comparative evaluation items of the reference drug and the test drug is within log 0.9 to log 1.11, and 2) the two drugs are equivalent under all stipulated conditions when a comparative dissolution test is conducted according to the Pharmaceutical Equivalence Test Standards.

[0051] In the present invention, the rivaroxaban of the pharmaceutical composition of the present invention may have a 45-minute dissolution rate of, for example, 55% or more, for example, 70% or more.

[0052] The rivaroxaban dissolution rate of the pharmaceutical composition according to the present invention is higher than the dissolution rate of rivaroxaban of a micronized rivaroxaban preparation. Here, the micronized rivaroxaban preparation refers to a product approved by a pharmaceutical approval agency such as the Food and Drug Administration (FDA) or the Ministry of Food and Drug Safety. For example, the approved micronized rivaroxaban preparation may be Xarelto tablets.

[0053] In the present invention, the pharmaceutical composition may be formulated into a tablet form and may be for oral administration.

[0054] In addition, the pharmaceutical composition according to the present invention may be formulated into tablets, and in this case, it may be coated with a coating agent as needed.

[0055] In the pharmaceutical composition according to the present invention, the content of rivaroxaban is not particularly limited. For example, the pharmaceutical composition of the present invention may be formulated with a dosage of 15 g to 30 g of rivaroxaban per unit dose, specifically 18 to 25 g.

[0056] In one embodiment of the present invention, the pharmaceutical composition may include 18 to 20 g of rivaroxaban.

[0057] In another embodiment of the present invention, the pharmaceutical composition may have a dosage form of a tablet, a mini tablet, and / or a pellet-containing capsule.

[0058] The pharmaceutical composition including rivaroxaban according to the present invention may be used for reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation, treating deep vein thrombosis and pulmonary embolism, reducing the risk of recurrence of deep vein thrombosis and pulmonary embolism, or preventing venous thromboembolism.

[0059] In addition to the active ingredient, the pharmaceutical composition of the present invention contains one or more additives.

[0060] Diluents increase the volume of a solid pharmaceutical composition, thereby making it easier for patients and caregivers to handle pharmaceutical dosage forms containing the composition. Diluents for solid compositions include, for example, microcrystalline cellulose, microfine cellulose, lactose, lactose hydrate, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugars, dextrate, dextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylates (e.g., Eudragit®), potassium chloride, powdered cellulose, sodium chloride, sorbitol, and talc.

[0061] Solid pharmaceutical compositions compressed into a dosage form, such as a tablet, may include additives which help bind the active ingredient and other excipients together after compression. Binders for solid pharmaceutical compositions include acacia, alginic acid, carbomer (e.g., Carbopol), sodium carboxymethylcellulose, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenated vegetable oils, hydroxyethyl cellulose, hydroxypropyl cellulose (e.g., Klucel®), hydroxypropyl methylcellulose (e.g., Methocel®), liquid glucose, magnesium aluminum silicate, maltodextrin, methylcellulose, polymethacrylates, povidone (e.g., Kollidon®and Plasdone®), pregelatinized starch, sodium alginate, and starch.

[0062] Disintegrants may be added to the composition to increase the dissolution rate of the compressed solid pharmaceutical composition within a patient's stomach. Disintegrants include hydroxypropyl cellulose, carboxymethylcellulose calcium, carboxymethylcellulose sodium (e.g., Ac-Di-Sol®and Primellose®), microcrystalline cellulose, methyl cellulose, powdered cellulose, colloidal silicon dioxide, croscarmellose sodium, crospovidone (e.g., Kollidon®and Polyplasdone®), guar gum, magnesium aluminum silicate, polacrilin potassium, pregelatinized starch, alginic acid, sodium alginate, sodium starch glycolate (e.g., Explotab®), and starch.

[0063] When a powder composition is compressed to prepare a dosage form, such as a tablet, the composition is subjected to pressure from a punch and a die. Some excipients and active ingredients tend to adhere to the surfaces of the punch and die, which may cause the product to have pitting and other surface irregularities. A lubricant may be added to the composition to reduce adhesiveness and facilitate release of the product from the die. Lubricants include stearic acid salts such as magnesium stearate, calcium stearate, aluminum stearate, and zinc stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oils, hydrogenated vegetable oils, mineral oils, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, talc, and the like.

[0064] To improve storage stability, preservatives and chelating agents such as alcohols, sodium benzoate, butylated hydroxytoluene, butylated hydroxyanisole, and ethylenediaminetetraacetic acid may be added at levels safe for consumption.

[0065] The present invention also provides a use for reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation, treating deep vein thrombosis and pulmonary embolism, reducing the risk of recurrence of deep vein thrombosis and pulmonary embolism, or preventing venous thromboembolism, including administering the pharmaceutical composition to a subject in need thereof.

[0066] In the present invention, the term 'subject' refers to a warm-blooded animal such as a mammal suffering from a specific disease, disorder, or condition, and includes a human, an orangutan, a chimpanzee, a mouse, a rat, a dog, a cow, a chicken, a pig, a goat, a sheep, and the like, but is not limited thereto.

[0067] In the present invention, the term 'treatment' includes alleviating symptoms, temporarily or permanently eliminating the cause of symptoms, or preventing or slowing down the appearance of symptoms and the progression of a disease, disorder, or condition, but is not limited thereto.

[0068] In the pharmaceutically acceptable salts of the present invention, the 'salt' may be an acid addition salt formed by a pharmaceutically acceptable free acid. The acid addition salts are obtained from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, and phosphorous acid, and non-toxic organic acids such as aliphatic monocarboxylates and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and alkanedioates, aromatic acids, and aliphatic and aromatic sulfonic acids. These pharmaceutically non-toxic salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphate chlorides, bromides, iodides, fluorides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caprates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyn-1,4-dioates, hexane-1,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chlorobenzenesulfonates, xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, β-hydroxybutyrates, glycolates, malates, tartrates, methanesulfonates, propanesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, or mandelates.

[0069] The acid addition salt according to the present invention may be prepared by a conventional method, for example, by dissolving a compound in an excess of an aqueous acid solution and precipitating a salt thereof using a water-miscible organic solvent, for example, methanol, ethanol, acetone, or acetonitrile. It may also be prepared by evaporating the solvent or the excess of acid from the mixture and then drying the salt, or by suction-filtering the precipitated salt.

[0070] In addition, a pharmaceutically acceptable metal salt may be prepared using a base. An alkali metal or alkaline earth metal salt is obtained, for example, by dissolving a compound in an excess of an alkali metal hydroxide or an alkaline earth metal hydroxide solution, filtering the undissolved compound salt, and evaporating and drying the filtrate. At this time, preparing a sodium, potassium, or calcium salt as the metal salt is pharmaceutically suitable. A silver salt corresponding thereto is obtained by allowing an alkali metal or alkaline earth metal salt to react with a suitable silver salt (e.g., silver nitrate).

[0071] The effective amount of the active ingredient of the pharmaceutical composition of the present invention refers to the amount required to treat a disease. Therefore, it may be adjusted according to various factors including the type of disease, the severity of the disease, the type and content of the active ingredient and other ingredients contained in the composition, the type of dosage form, and the patient's age, weight, general health state, sex and diet, administration time, administration route and excretion rate of the composition, treatment duration, and concurrently used drugs. For example, the pharmaceutical composition of the present invention may be administered 1 to 3 times a day and may be taken at the dosage per unit dose exemplified above, but is not limited thereto.

[0072] The present invention also provides a method of treating thromboembolic disorders comprising administering the pharmaceutical composition described herein to a subject in need thereof.

[0073] In the present invention, the term "thromboembolic disorder" may refer to any disease in which a thrombus forms in the blood and travels through the vasculature as an embolism, thereby blocking blood flow or pathologically affecting the circulatory system, but is not limited thereto.

[0074] In the present invention, thromboembolic disorder may refer to one or more selected from the group consisting of the following, but not limited thereto:

[0075] the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation;

[0076] deep vein thrombosis (DVT);

[0077] pulmonary embolism (PE);

[0078] the risk of recurrence of DVT and / or PE;

[0079] DVT which may lead to PE in patients undergoing knee or hip replacement surgery;

[0080] venous thromboembolism (VTE) in acutely ill medical patients at risk for thromboembolic complications not at high risk of bleeding;

[0081] the risk of major cardiovascular events (cardiovascular death, myocardial infarction, and stroke) in patients with coronary artery disease (CAD);

[0082] the risk of major thrombotic vascular events (myocardial infarction, ischemic stroke, acute limb ischemia, and major amputation of a vascular etiology) in patients with peripheral artery disease (PAD), including those after lower extremity revascularization;

[0083] VTE and the risk of recurrent VTE in pediatric patients from birth to less than 18 years of age after initial anticoagulation; and

[0084] thrombosis in pediatric patients aged 2 years and older with congenital heart disease who have undergone the Fontan procedure.

[0085] In the present invention, Rivaroxaban may have the effects and efficacies of, but is not limited thereto:

[0086] reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation;

[0087] treating deep vein thrombosis (DVT);

[0088] treating pulmonary embolism (PE);

[0089] reducing the risk of recurrence of DVT and / or PE;

[0090] preventing DVT which may lead to PE in patients undergoing knee or hip replacement surgery;

[0091] preventing venous thromboembolism (VTE) in acutely ill medical patients at risk for thromboembolic complications not at high risk of bleeding;

[0092] reducing the risk of major cardiovascular events (cardiovascular death, myocardial infarction, and stroke) in patients with coronary artery disease (CAD);

[0093] reducing the risk of major thrombotic vascular events (myocardial infarction, ischemic stroke, acute limb ischemia, and major amputation of a vascular etiology) in patients with peripheral artery disease (PAD), including those after lower extremity revascularization;

[0094] treating VTE and reducing the risk of recurrent VTE in pediatric patients from birth to less than 18 years of age after initial anticoagulation; and

[0095] preventing thrombosis in pediatric patients aged 2 years and older with congenital heart disease who have undergone the Fontan procedure.

[0096] The present invention also provides use of the composition described herein for the manufacture of a medicament for treating thromboembolic disorders.

[0097] According to the present invention, by selecting an appropriate range of rivaroxaban particle size and hydrophilic polymer content, it is possible to provide a rivaroxaban composition having bioavailability independent of the presence or absence of food, while using microscale rivaroxaban particles.

[0098] FIG. 1 shows a graph illustrating the average dissolution rate of a Xarelto tablet.

[0099] FIG. 2 shows a graph illustrating the average dissolution rate of the tablets of Examples 1 and 2.

[0100] FIG. 3 shows a graph illustrating the average dissolution rate of the tablets of Examples 3 to 5.

[0101] FIG. 4 shows a graph illustrating the average dissolution rate of the tablets of Examples 6 to 8.

[0102] FIG. 5 shows graphs comparing the average dissolution rate of the tablet of Example 7 and the Xarelto tablet.

[0103] The advantages and features of the present invention and the methods for achieving them will become clear with reference to the examples described in detail below. However, the present invention is not limited to the examples disclosed below but may be implemented in various different forms, and these examples are provided only to make the disclosure of the present invention complete and to fully inform a person having ordinary skill in the art to which the present invention pertains of the scope of the invention, and the present invention is defined only by the scope of the claims.

[0104]

[0105] [Examples]

[0106] Preparation Examples 1 to 8: Preparation of dispersions having different rivaroxaban particle sizes

[0107] [Table 1]

[0108]

[0109] [Table 2]

[0110]

[0111]

[0112] Rivaroxaban formulations having different particle sizes were prepared using the compositions of Preparation Examples 1 to 8 of Table 1 above. All additives except rivaroxaban have the property of dissolving in purified water. Hydrophilic polymers such as hypromellose (hydroxypropyl methylcellulose; HPMC), povidone, and copovidone were dispersed in purified water, and surfactants such as poloxamer and sodium lauryl sulfate were dispersed and dissolved clearly.

[0113] Preparation Examples 1 to 8 were prepared by adding rivaroxaban to a dispersion, mixing it homogeneously, and then pulverizing the resulting mixture 10 times under high-energy conditions (1,000 to 2,000 bar) using a high-pressure particle dispersion device (Microfluidics) to prepare micronized rivaroxaban particles having different particle sizes.

[0114] The particle size of the micronized rivaroxaban was measured using a laser scattering particle size analyzer (Mastersizer 2000, Malvern Instruments). When measuring the particle size, a beaker (1,000 ml) was filled with purified water, micronized rivaroxaban particles were added while stirring at 1,500 rpm, and measurement was performed with the homogeneously suspended dispersion phase. The results are shown in Table 3 below.

[0115] <Particle size measurement conditions>

[0116] - Device: Malvern Mastersizer 2000 / Hydro 2000MU

[0117] - Sample usage amount: 0.5 g

[0118] - Sample refractive index: 1.520

[0119] - Analysis model: General purpose

[0120] - Sensitivity: Normal

[0121] - Sample measurement time: 10 seconds

[0122] - Analysis range: 0.020 to 2000.0 μm

[0123]

[0124] [Table 3]

[0125]

[0126] As shown in Table 3 above, it was confirmed that when hydrophilic polymers and surfactants were dispersed at high pressure, the particle size could be improved to a similar level regardless of the type and amount thereof.

[0127]

[0128] Examples 1 and 2: Manufacture of tablets having different rivaroxaban particle sizes

[0129] The dispersions of Preparation Examples 7 and 8 having different rivaroxaban particle sizes were formulated into tablets with the compositions shown in Table 4 below to manufacture Examples 1 and 2, respectively.

[0130] [Table 4]

[0131]

[0132] Preparation of rivaroxaban tablets (units: g)

[0133]

[0134] [Table 5]

[0135]

[0136]

[0137] Sodium lauryl sulfate and hypromellose were dispersed in the purified water of Table 4 above and dissolved clearly. The dissolved dispersion phase was mixed with each of the dispersions of Preparation Examples 7 and 8 to prepare binding solutions. Thereafter, 70 g of d-mannitol and 10 g of crospovidone were placed in a fluid bed granulator and used as a carrier, and the binding solutions were sprayed to prepare fluid bed granules. The conditions for preparing the granules were an injection temperature of 70 to 85 ℃, a chamber temperature of 35 to 45 ℃, and an injection rate of 8 to 25 g / min. The prepared granules were well mixed with magnesium stearate and then tableted.

[0138]

[0139] Reference Example: Dissolution rate of Xarelto tablet

[0140] Xarelto tablets containing 20 mg of rivaroxaban were tested according to the Korean Pharmacopoeia Dissolution Test Method 2 (paddle method) using a dissolution device (manufacturer: Hanson). The dissolution test was performed using purified water as a dissolution medium at a paddle speed of 50 rpm at 37 ℃. The results were quantified using a high performance liquid chromatography (HPLC) system (manufacturer: Agilent) according to the liquid chromatography method under the following conditions, and the results are shown in Table 6 and FIG. 1 below.

[0141] <HPLC measurement conditions>

[0142] - Detector: UV spectrophotometer (measurement wavelength: 250 nm)

[0143] - Column: Column filled with octadecyl silylated silica gel (50 mm x 4.6 mm, 5 μm) or a similar column

[0144] - Flow rate: 1.0 mL / min

[0145] - Column temperature: 40 ℃

[0146] - Mobile phase: Acetonitrile:pH 4.3 phosphoric acid solution = 35:65 v / v%

[0147] - Injection amount: 20 μL

[0148] [Table 6]

[0149]

[0150] As a result of conducting a dissolution test of Xarelto tablets, the 45-minute mean dissolution rate was 40% (FIG. 1).

[0151]

[0152] Experimental Example 1: Changes in dissolution rate according to particle size

[0153] The tablets of Examples 1 and 2 were tested according using a dissolution device for the Korean Pharmacopoeia Dissolution Test (manufacturer: Hanson) according to the Korean Pharmacopoeia Dissolution Test Method 2 (paddle method). The dissolution test was performed using purified water as a dissolution medium at a paddle speed of 50 rpm at 37 ℃. The results were quantified using an HPLC system (manufacturer: Agilent) according to the liquid chromatography method under the following conditions, and the results are shown in Table 7 and FIG. 2 below.

[0154] [Table 7]

[0155]

[0156] As can be seen in Table 7 above and FIG. 2, Examples 1 and 2 showed a 45-minute mean dissolution rate of 60%, which was higher than that of Xarelto tablets. These results show that the mean dissolution rate (%) may be increased when the rivaroxaban particle size is reduced.

[0157]

[0158] Examples 3 to 5: Manufacture of tablets having different rivaroxaban particle sizes

[0159] In order to confirm the change in dissolution rate according to the difference in rivaroxaban particle size, each dispersion was prepared by adjusting the number of times of performing high-pressure dispersion as shown in Table 8 below with the composition of Preparation Example 8, and then tableted with the composition of Table 8 below to prepare each of Examples 3 to 5, thereby preparing micronized rivaroxaban having various particle sizes as shown in Table 9.

[0160] [Table 8]

[0161]

[0162] [Table 9]

[0163]

[0164]

[0165] Experimental Example 2: Changes in dissolution rate according to particle size

[0166] The tablets of Examples 3 to 5 were tested according using a dissolution device for the Korean Pharmacopoeia Dissolution Test (manufacturer: Hanson) according to the Korean Pharmacopoeia Dissolution Test Method 2 (paddle method). The dissolution test was performed using purified water as a dissolution medium at a paddle speed of 50 rpm at 37 ℃. The results were quantified using an HPLC system (manufacturer: Agilent) according to the liquid chromatography method under the following conditions, and the results are shown in Table 10 and FIG. 3.

[0167] [Table 10]

[0168]

[0169] As can be seen in Table 10 above and FIG. 3, Examples 3 and 4 exhibited increased dissolution rates compared to Xarelto tablets, but Example 5 exhibited a low dissolution rate. These results show that it is preferable in terms of dissolution rate to reduce the drug particle d(50) to at least 3 μm or less by high-pressure dispersion of rivaroxaban.

[0170]

[0171] Examples 6 to 8: Manufacture of rivaroxaban tablets having various hydrophilic polymer contents

[0172] Dispersions of rivaroxaban particles having a d(50) of 3 μm or less were prepared using the compositions in Table 11 below and the preparation methods of Examples 1 to 8. Thereafter, the dispersions were sprayed on d-mannitol and crospovidone to prepare wet granules using a fluidized bed granulator, the prepared granules were mixed with sodium stearyl fumarate, and the resulting mixture was tableted.

[0173] [Table 11]

[0174]

[0175]

[0176] [Table 12]

[0177]

[0178]

[0179] Experimental Example 3: Dissolution rate according to the amount of hydrophilic polymer

[0180] The tablets of Examples 6 to 8 were tested according using a dissolution device for the Korean Pharmacopoeia Dissolution Test (manufacturer: Hanson) according to the Korean Pharmacopoeia Dissolution Test Method 2 (paddle method). The dissolution test was performed using purified water as a dissolution medium at a paddle speed of 50 rpm at 37 ℃. The results were quantified using an HPLC system (manufacturer: Agilent) according to the liquid chromatography method under the following conditions, and the results are shown in Table 13 and FIG. 4 below.

[0181] [Table 13]

[0182]

[0183]

[0184] As can be seen in Table 13 above and FIG. 4, the dissolution rates of Examples 6 to 8 were evaluated to be at the level of 70% to 80%. These results show that the use of a hydrophilic polymer is preferable in terms of improving the dissolution rate, and this may be because the hydrophilic polymer suppresses the re-agglomeration of the micronized main component exposed to the aqueous solution.

[0185]

[0186] Experimental Example 4: Evaluation of dissolution rate in simulated intestinal fluids

[0187] The tablets of Example 7 and Xarelto tablets were tested by the Korean Pharmacopoeia Dissolution Test Method 2 (paddle method). The dissolution solutions were a fasted state simulated intestinal fluid (FaSSIF, 3 mM sodium taurocholate, 0.75 mM lecithin, 0.174 g NaOH, 1.977 g NaH2PO4·H2O), 3.093 g NaCl, 500 mL purified water) and a fed state simulated intestinal fluid (FeSSIF, 15 mM sodium taurocholate, 3.75 mM lecithin, 4.04 g NaOH, 8.65 g glacial acetic acid, 11.874 g NaCl, 1,000 mL purified water), and the dissolution test was performed at 50 rpm and 37 ℃. The results were quantified by HPLC and shown in Table 14 and FIG. 5 below.

[0188] [Table 14]

[0189]

[0190]

[0191] As can be seen in Table 14 above and FIG. 5, the dissolution rate of Xarelto tablets, which are affected by food, in the FaSSIF was lower than that in FeSSIF. Example 7 exhibited an improved dissolution rate compared to the Xarelto tablet in each dissolution solution, and at the same time, Example 7 exhibited a similar dissolution rate regardless of the type of dissolution solution, and therefore, it was confirmed that bioavailability could be improved regardless of food.

[0192]

[0193] Experimental Example 5: Blood concentration comparison test

[0194] Pharmacotoxicological parameters were measured in 36 healthy subjects. The measurement was performed using an open, randomized, single-dose, 2-group, 2-period crossover design to evaluate the effect of food on stability and pharmacokinetics. After administering rivaroxaban to healthy subjects before and after meals, the blood concentration of rivaroxaban in the body was measured within 34 hours and statistically analyzed to obtain the AUC and Cmax. The analytical results are shown in Table 15 below.

[0195] [Table 15]

[0196]

[0197]

[0198] Regarding the pharmaceutical equivalence, according to the bioequivalence test of the Pharmaceutical Equivalence Test Standards of the Collection of Pharmaceutical Affairs Laws and Regulations, when the AUC and the Cmaxof the reference drug and the test drug are log-transformed, when both items satisfy the condition that the difference in the log-transformed means is within log 0.8 to log 1.25 at a 90% confidence interval, the test drug is considered equivalent in the pharmaceutical equivalence test. From the above-described results, it was confirmed that the preprandial / postprandial bioavailability of the pharmaceutical composition including the micronized rivaroxaban according to the present invention was equivalent.

Claims

1.A pharmaceutical composition comprising micronized rivaroxaban, a pharmaceutically acceptable salt thereof, and a hydrophilic polymer,wherein particles of the micronized rivaroxaban have a d(50) value of 3 μm or less.2.The pharmaceutical composition of claim 1, wherein the particles of the micronized rivaroxaban have a d(90) value of 6 μm or less.3.The pharmaceutical composition of claim 1, wherein the hydrophilic polymer is one or more selected from the group consisting of hypromellose, povidone, copovidone, polyvinylpyrrolidone, polyethylene glycol, a copolymer of vinylpyrrolidone-vinylacetate, hydroxypropyl cellulose, hydroxyethyl cellulose, polyvinyl alcohol, and a methacrylate copolymer.4.The pharmaceutical composition of claim 1, wherein the hydrophilic polymer is one or more selected from the group consisting of hypromellose, povidone, and copovidone.5.The pharmaceutical composition of claim 1, wherein the hydrophilic polymer is included in an amount of 0.25 to 0.8 parts by weight based on 1 part by weight of the micronized rivaroxaban.6.The pharmaceutical composition of claim 1, further comprising a surfactant.7.The pharmaceutical composition of claim 6, wherein the surfactant is one or more selected from the group consisting of poloxamer, sodium lauryl sulfate, a docusate salt, sucrose, a stearate salt, a cetyltrimethylammonium salt, fatty alcohol ethoxylate, glycerol monostearate, glycerol monolaurate, sorbitan monolaurate, sorbitan monostearate, sorbitan monooleate, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monostearate, and polyoxyethylene monooleate.8.The pharmaceutical composition of claim 6, wherein the surfactant is included in an amount of 0.05 to 0.15 parts by weight based on 1 part by weight of the micronized rivaroxaban.9.The pharmaceutical composition of claim 1, wherein the pharmaceutical composition exhibits bioequivalence when administered to a person in a postprandial state compared to administration to a person in a fasting state, andthe bioequivalence satisfies conditions:(i) Cmaxis within log 0.8 to log 1.25 at a 90% confidence interval, and(ii) an area under curve (AUC) is within log 0.8 to log 1.25 at a 90% confidence interval.10.The pharmaceutical composition of claim 1, wherein the pharmaceutical composition including the micronized rivaroxaban has a 45-minute rivaroxaban dissolution rate higher than or equal to 55% measured in a fasted state simulated intestinal fluid and a fed state simulated intestinal fluid.11.The pharmaceutical composition of any one of claims 1 to 10, wherein the pharmaceutical composition is formulated into a tablet form and is for oral administration.12.A method of treating thromboembolic disorders comprising administering the pharmaceutical composition of any one of claim 1 to 11 to a subject in need thereof.13.Use of the composition of any one of claim 1 to 11 for the manufacture of a medicament for treating thromboembolic disorders.

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