KR102282186B1 - A solubilized composition comprising rivaroxaban - Google Patents

Abstract

The present invention relates to a solubilizing composition comprising rivaroxaban, and specifically, by improving solubility of rivaroxaban, dissolution rate and bioavailability are increased, and oral pharmaceutical composition capable of rapidly releasing rivaroxaban and to a method for preparing the same.

Description

Solubilized composition comprising rivaroxaban {A solubilized composition comprising rivaroxaban}

Cross-Citation with Related Applications

This application claims the benefit of priority based on Korean Patent Application No. 10-2018-0114068 on September 21, 2018, and all contents disclosed in the literature of the Korean patent application are incorporated as a part of this specification.

The present invention relates to a solubilizing composition comprising rivaroxaban, and specifically, by improving solubility of rivaroxaban, dissolution rate and bioavailability are increased, and oral pharmaceutical composition capable of rapidly releasing rivaroxaban and to a method for preparing the same.

Rivaroxaban is marketed ^{under the trade name of Xarelto TM} , and the efficacy and effect of rivaroxaban are 1) reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation, 2) deep vein thrombosis and pulmonary embolism. 3) reduction of risk of recurrence of deep vein thrombosis and pulmonary embolism, 4) prevention of venous thromboembolism in adult patients who have undergone major orthopedic surgery of the lower extremity (knee or total hip arthroplasty), and 5) elevation of cardiac biomarkers. It is a reduction in the incidence of atherosclerotic events (death due to cardiovascular disease, myocardial infarction) when administered in combination with aspirin or with aspirin and clopidogrel in patients who have experienced acute coronary syndrome with

Rivaroxaban has a very low water solubility of about 7 mg/L and is known to have high oral biological deviation. Bayer, the original developer of rivaroxaban, a poorly soluble drug, disclosed in Korean Patent No. 10-1151117, a pharmaceutical composition in a hydrophilized form prepared through wet granulation to improve solubility and dissolution rate, and its A manufacturing method is disclosed. However, the solubility improvement of ^{Xarelto TM} tablets, a commercially available rivaroxaban formulation marketed through the application of this technology, is not sufficient. The dosing regimen was set as what should be administered.

Therefore, in order to improve these disadvantages, it is necessary to increase the solubility of the poorly soluble drug rivaroxaban to a greater extent, and various solubilization technologies for this purpose have been developed.

Korean Patent Application Laid-Open No. 2016-0004483 discloses a method for preparing a solubilized formulation through spray drying and wet granulation. Specifically, rivaroxaban, a sparingly soluble drug, is suspended in a mixed solvent of ethanol and water in which hydroxypropylmethyl cellulose (HPMC) is dissolved, and a powder is prepared by spray drying, and the powder is mixed with other additives and wetted. As a technology for manufacturing tablets through granulation, sodium lauryl sulfate (SLS), etc. as a solubilizer of rivaroxaban was mixed with granules and then tableted to prepare tablets. In addition, Korean Patent Application Laid-Open No. 10-2016-0082170 discloses a rivaroxaban tablet formulation prepared by wet granulation. Specifically, tablets containing rivaroxaban, polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (soluplus), SLS, and additives were prepared through wet granulation. This preparation method is a method for preparing a composition in a general tablet form, and since rivaroxaban is a material with low solubility in a pharmaceutically acceptable solvent, only a solubilization effect through contact of the hydrophilic additive and rivaroxaban can be expected. Therefore, the solubility improvement effect of rivaroxaban is not excellent compared to the previous technology.

Korean Patent Registration No. 10-1499867 discloses a method of solubilizing rivaroxaban in an amorphous form through melt extrusion. As a water-soluble polymer, a solid dispersion containing rivaroxaban was prepared through melt extrusion using a vinylpyrrolidone-vinyl acetate copolymer (PVPVA64) or a polymer thereof and vitamin E-TPGS. In addition, Korea Patent No. 10-1535586 discloses a pharmaceutical composition containing rivaroxaban and PVPVA64 prepared through melt extrusion and a method for preparing the same. The patent discloses a method for preparing a solid dispersion containing amorphous rivaroxaban by thermally melting a poorly soluble drug without using a solvent instead of an amorphous transformation method through a solution preparation using a solvent, but rivaroxaban Silver has a melting point of about 220 ° C and is unstable to heat, so there is a risk of decomposition by heat applied during the process of preparing a solubilizing composition by thermal melt extrusion method to generate decomposition products, so it is difficult to apply as a practical pharmaceutical manufacturing process. There are disadvantages.

Republic of Korea Patent Publication No. 2016-0004483 Korean Patent Registration No. 10-1499867 Korean Patent Registration No. 10-1535586

Under this background, the present inventors have made an earnest effort to overcome the dissolution properties of rivaroxaban, which is known to be difficult to amorphize through solution preparation due to poor solubility, as a result of using a cationic polymer or cationic polymer and acid, rivaroxaban The present invention was completed by developing an amorphous manufacturing method through the preparation of a mixed solution. Accordingly, it has become possible to provide a pharmaceutical composition containing rivaroxaban, which has increased bioavailability and exhibits excellent stability.

The present invention, (a) preparing a solution comprising a solvent, rivaroxaban (Rivaroxaban) and a pharmaceutically acceptable cationic polymer; and

(b) converting said solution into a pharmaceutical composition.

The present invention provides an oral pharmaceutical composition prepared by the above preparation method.

The present invention, comprising rivaroxaban and a pharmaceutically acceptable cationic polymer, to provide an oral pharmaceutical composition.

The present invention provides a method for preventing or treating thromboembolic disease by administering a pharmaceutical composition comprising rivaroxaban and a pharmaceutically acceptable cationic polymer to a subject in need of treatment.

The present invention provides the use of a pharmaceutical composition comprising rivaroxaban and a pharmaceutically acceptable cationic polymer for the manufacture of a medicament for the prevention or treatment of thromboembolic diseases.

The present invention provides the use of a pharmaceutical composition comprising rivaroxaban and a pharmaceutically acceptable cationic polymer for the prevention or treatment of thromboembolic diseases.

This will be described in detail as follows. Meanwhile, each description and embodiment disclosed in the present invention may be applied to each other description and embodiment. That is, all combinations of the various elements disclosed herein fall within the scope of the present invention. In addition, it cannot be considered that the scope of the present invention is limited by the specific descriptions described below.

One aspect of the present invention is

(a) preparing a solution containing a solvent, rivaroxaban (Rivaroxaban) and a pharmaceutically acceptable cationic polymer; and

(b) converting said solution into a pharmaceutical composition.

Another aspect of the present invention is an oral pharmaceutical composition prepared by the above method. The oral pharmaceutical composition includes rivaroxaban and a pharmaceutically acceptable cationic polymer.

Rivaroxaban (RXB) in the present invention has a structure of the following formula 1, (S)-5-chloro-N-{[2-oxo-3-[4-(3-oxomorpholine-4- yl)phenyl]oxazolidin-5-yl]methyl}thiophene-2-carboxamide.

[Formula 1]

In an embodiment of the present invention, pharmaceutically acceptable cationic polymers include, but are not limited to, polyvinylacetaldiethylaminoacetic acid (AEA), dimethylaminoethyl methacrylate-methyl methacrylate copolymer (Eudragit E) , chitosan (CS), polyethyleneimine (PEI), poly-L-lysine (PLL), or a mixture of two or more thereof.

In an embodiment of the present invention, the solution may further contain an acid. In embodiments of the present invention, but not limited thereto, acids include hydrochloric acid, citric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, maleic acid, fumaric acid, tartaric acid, malic acid, oxalic acid, methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid Or it may be a mixture of two or more of them, specifically citric acid.

As an embodiment of the composition according to an embodiment of the present invention, the weight ratio of rivaroxaban and the cationic polymer is 1: 0.5 to 1: 10, specifically 1: 2.5 to 1: 5 may be, rivaroxaban and acid The weight ratio may be 1: 0.1 to 1: 2, specifically 1: 0.2 to 1: 1.5, and more specifically, 1: 0.2 to 1: 1.2, but the scope of the present invention is not limited thereto.

In the present invention, it was confirmed that the poorly soluble drug rivaroxaban can be completely dissolved in a solvent together with a pharmaceutically acceptable cationic polymer and acid, and also the dissolution rate of rivaroxaban by preparing a pharmaceutical composition from the prepared solution , it was confirmed that the bioavailability was significantly increased, and the production of related substances was further reduced.

Each step of the manufacturing method will be described in detail as follows.

Step (a) is a step of preparing a solution containing rivaroxaban and a pharmaceutically acceptable cationic polymer.

In an embodiment of the present invention, the solution may further contain an acid.

In an embodiment of the present invention, preparing the solution may include dissolving rivaroxaban and a cationic polymer or rivaroxaban, a cationic polymer and an acid in a solvent.

Here, the solvent may be water, methanol, ethanol, isopropanol, acetone, acetonitrile, dichloromethane, tetrahydrofuran, or a mixture of two or more thereof, but is not limited thereto. For example, the solvent may be a mixture of dichloromethane and ethanol, and in this case, the mixture may have a ratio by weight of dichloromethane and ethanol of 9: 1 to 1 : 9, but is not limited thereto. In a specific example of the present invention, dichloromethane and ethanol were used in a ratio of 4 : 1 by weight, and it was confirmed that rivaroxaban, a poorly soluble drug, was completely dissolved under all the Example conditions. In the present invention, "completely dissolved" means that a clear solution is formed, and can be clearly distinguished from suspension, colloid, or solid agglomeration and precipitation.

Step (b) is the step of converting the dissolved solution into a pharmaceutical composition.

In the present invention, the step of converting into a pharmaceutical composition means any method known in the art for preparing a pharmaceutical composition using a solution containing an active ingredient.

In an embodiment of the present invention, the solution containing rivaroxaban and a pharmaceutically acceptable cationic polymer and acid, prepared in step (a), is prepared in various pharmaceutical compositions, for example, spray drying, fluidized bed. It may be applied to a method, a rotary evaporation method, a co-precipitation method, a supercritical fluid method, or the like, or a pan coater may be applied, but is not limited thereto. Through this process, the crystalline form of rivaroxaban is converted to an amorphous form, thereby significantly improving solubility. For example, in the case of using a fluidized bed method, a pharmaceutical composition may be formed by forming a fluidized bed with pharmaceutically acceptable additive spherical granules or the like, and then spraying the solution formed in step (a) onto the fluidized bed.

In an embodiment of the present invention, the oral pharmaceutical composition according to the present invention is a solid dispersion powder of rivaroxaban, granules, capsules or tablets containing the solid dispersion, or rivaroxaban-coated pellets (spherical granules) or in the form of film-coated tablets. For example, solid dispersion powder and granules containing the solid dispersion may be formulated as granules, powders, capsules, tablets, etc., but is not limited thereto. In addition, in this case, pharmaceutically acceptable additives, for example, diluents, binders, excipients, disintegrants, lubricants, etc. may be additionally used in order to be molded into an appropriate form, but is not limited thereto.

As an embodiment of the composition according to an embodiment of the present invention, converting the solution into a pharmaceutical composition may include spraying the solution to prepare a solid dispersion of rivaroxaban. Here, the solid dispersion may be a powder or granules, and in this case, rivaroxaban may be amorphous. In addition, the spraying of the solution may be performed using a spray dryer or a fluidized bed granulator. The rivaroxaban solid dispersion in the powder state may be filled in a capsule with a pharmaceutically acceptable additive to prepare a capsule, mixed with a pharmaceutically acceptable excipient, disintegrant, or lubricant, tableted and coated Tablets may be prepared.

As another embodiment of the composition according to the embodiment of the present invention, the step of converting the solution into a pharmaceutical composition may include the step of coating the solution by spraying the solution on spherical granules in a fluid state. Here, the rivaroxaban may be amorphous, and the coating may be performed using a fluidized bed granulator.

As another embodiment of the composition according to the embodiment of the present invention, the step of converting the solution into a pharmaceutical composition may include spraying the solution onto the core tablet and coating it. Here, the rivaroxaban may be amorphous, and the coating may be performed using a pan coater. Specifically, the pan coater may be a pan coater in which the core tablet forms a fluidized bed or a pan coater in which the core tablet does not form a fluidized bed, and more specifically, it may be a pan coater in which the core tablet does not form a fluidized bed. .

As a specific embodiment, the method for preparing the oral pharmaceutical composition includes (a) rivaroxaban, polyvinylacetaldiethylaminoacetic acid (AEA) and preparing a coating solution by dissolving citric acid; and (b) putting the core tablet (placebo tablet) into a pan coater and spraying the prepared coating solution to prepare a film-coated tablet. In this case, the pan coater may not form a fluidized bed, or the pan coater may form a fluidized bed, and specifically, the pan coater may not form a fluidized bed.

Another aspect of the present invention provides an oral pharmaceutical composition comprising rivaroxaban prepared by the method described above.

In an embodiment of the present invention, the rivaroxaban in the oral pharmaceutical composition prepared by the method may be amorphous.

Another aspect of the present invention is an oral pharmaceutical composition comprising rivaroxaban and a pharmaceutically acceptable cationic polymer.

In an embodiment of the present invention, the oral pharmaceutical composition may further comprise an acid.

According to an embodiment of the present invention, the pharmaceutical composition may further include a pharmaceutically acceptable additive.

In the oral pharmaceutical composition, rivaroxaban, cationic polymer, acid, and additives are the same as described above.

According to an embodiment of the present invention, the pharmaceutical composition may be a solid dispersion, granules, powders, capsules, tablets, spherical granules or film-coated tablets.

Pharmaceutical compositions containing rivaroxaban provided according to embodiments of the present invention exhibit improved solubility and dissolution rate. Specifically, the oral pharmaceutical composition prepared through the preparation method of the present invention is a dissolution test condition in which 300 mL of an eluate having a pH of 4.5 is used as a dissolution medium and the paddle is rotated at 150 rpm, 4 hours after the start of the test The release concentration of rivaroxaban is improved to two times or more compared to the rivaroxaban fine particles, and the elution concentration may be maintained, but is not limited thereto.

In a specific embodiment of the present invention, the rivaroxaban bioavailability of the rivaroxaban solid dispersion tablet (Example 70) prepared according to the present invention is significantly increased compared to the commercially available Xarelto tablet (Comparative Example 2) confirmed that it was. (Table 20 and Figure 5; AUC _0-12h about 3-5 times, and C _max about 3-5 times)

Another aspect of the present invention relates to a method for preventing or treating thromboembolic disease by administering to a subject in need thereof a pharmaceutical composition comprising rivaroxaban and a pharmaceutically acceptable cationic polymer.

Another aspect of the present invention relates to the use of a pharmaceutical composition comprising rivaroxaban and a pharmaceutically acceptable cationic polymer for the manufacture of a medicament for the prevention or treatment of thromboembolic diseases.

Another aspect of the present invention relates to the use of a pharmaceutical composition comprising rivaroxaban and a pharmaceutically acceptable cationic polymer for the prevention or treatment of thromboembolic diseases.

The present invention can provide rivaroxaban-containing pharmaceuticals with improved solubility of rivaroxaban, exhibiting excellent dissolution rate and bioavailability, and securing sufficient stability.

1 is a dissolution test result of the solid dispersion according to Example 3, Example 14 and Example 15 and Comparative Example 1 (micronized).
2 is a dissolution test result of the solid dispersion according to Example 3 and Example 16.
3 is a diagram showing a powder X-ray diffraction analysis pattern of the rivaroxaban powder of Comparative Example 1 and the rivaroxaban-containing solid dispersion prepared in Example 3; 3, the horizontal axis is 2θ (°), and RXB means rivaroxaban.
4 is a tablet containing rivaroxaban-containing solid dispersion prepared in Example 70, Comparative Example 2 (Xarelto 20 mg), and Comparative Example 3 (composition prepared according to Example 1 of Korean Patent No. 10-1535586) ) is the dissolution comparison result.
5 is a pharmacokinetic test result of Example 70 and Comparative Example 2.

Hereinafter, the present invention will be described in more detail through examples. However, these examples are for illustrative purposes only and the scope of the present invention is not limited to these examples.

Comparative Example 1: Rivaroxaban fine particle raw material

The size of the rivaroxaban micronized particles (Alembic Pharmaceuticals, Rivaroxaban ^® ) used as Comparative Example 1 in the present invention is shown in Table 1 below.

D (10) 2.0 microns D (50) 4.2 microns D (90) 8.5 microns

Comparative Example 2: Xarelto ^TM 20 mg tablet

Comparative Example 3: Rivaroxaban solid dispersion according to Example 1 (rivaroxaban + vinylpyrrolidone-vinyl acetate copolymer (PVPVA64)) of Korean Patent No. 10-1535586

Rivaroxaban and PVPVA64 in a mass ratio of 1: 3, using a melt extrusion method at 200 ℃ temperature to prepare a rivaroxaban solid dispersion.

Examples 1 to 68: Rivaroxaban solid dispersion solubilized through spray drying

According to the composition of Tables 2 to 6, a solid dispersion containing rivaroxaban was prepared by spray-drying (Examples 1 to 68). As the rivaroxaban, the raw material of rivaroxaban of Comparative Example 1 was used. Examples 1 to 68 include rivaroxaban and, a cationic polymer, and further include an acid if necessary. Specifically, as a cationic polymer, polyvinylacetaldiethylaminoacetic acid (AEA), dimethylaminoethyl methacrylate-methylmethacrylate copolymer (Eudragit E), chitosan (CS), polyethyleneimine (PEI) or poly-L-lysine ( PLL), acids include hydrochloric acid, citric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, maleic acid, fumaric acid, oxalic acid, methanesulfonic acid, benzenesulfonic acid, or toluenesulfonic acid. After completely dissolving rivaroxaban and cationic polymer or rivaroxaban, cationic polymer and acid in a mixed solvent of dichloromethane (80 parts by weight relative to rivaroxaban) and ethanol (20 parts by weight relative to rivaroxaban), spray A powder of rivaroxaban solid dispersion was prepared using a dryer (Spray Dryer; Buchi 290-B, Switzerland; Aspirator 100%, supply air temperature 60 ± 10 ℃, spray rate 10 ± 2 mL/min).

Example One 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 Rivaroxaban (g) One One One One One One One One One One One One One One One One Cationic polymer (g) AEA 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 5 acid (g) Hydrochloric acid - 0.1 - - - - - - - - - - - - - - citric acid - - 0.6 - - - - - - - - - - 0.37 1.11 One hydrobromic acid - - - 0.35 - - - - - - - - - - - - sulfuric acid - - - - 0.1 - - - - - - - - - - - phosphoric acid - - - - - 0.1 - - - - - - - - - - nitric acid - - - - - - 0.2 - - - - - - - - - maleic acid - - - - - - - 0.6 - - - - - - - - fumaric acid - - - - - - - - 0.6 - - - - - - - oxalic acid - - - - - - - - - 0.6 - - - - - - methanesulfonic acid - - - - - - - - - - 0.6 - - - - - Benzenesulfonic acid - - - - - - - - - - - 0.6 - - - - toluenesulfonic acid - - - - - - - - - - - - 0.6 - - -

Example 17 18 19 20 21 22 23 24 25 26 27 28 29 Rivaroxaban (g) One One One One One One One One One One One One One Cationic polymer (g) Eudragit E. 3 3 3 3 3 3 3 3 3 3 3 3 3 Acid (g) Hydrochloric acid - 0.225 - - - - - - - - - - - citric acid - - 0.6 - - - - - - - - - - hydrobromic acid - - - 0.75 - - - - - - - - - sulfuric acid - - - - 0.225 - - - - - - - - phosphoric acid - - - - - 0.225 - - - - - - - nitric acid - - - - - - 0.45 - - - - - - maleic acid - - - - - - - 0.6 - - - - - fumaric acid - - - - - - - - 0.6 - - - - oxalic acid - - - - - - - - - 0.6 - - - methanesulfonic acid - - - - - - - - - - 0.6 - - Benzenesulfonic acid - - - - - - - - - - - 0.6 - toluenesulfonic acid - - - - - - - - - - - - 0.6

Example 30 31 32 33 34 35 36 37 38 39 40 41 42 Rivaroxaban (g) One One One One One One One One One One One One One Cationic polymer (g) CS 3 3 3 3 3 3 3 3 3 3 3 3 3 acid (g) Hydrochloric acid - 0.275 - - - - - - - - - - - citric acid - - 0.6 - - - - - - - - - - hydrobromic acid - - - 0.875 - - - - - - - - - sulfuric acid - - - - 0.275 - - - - - - - - phosphoric acid - - - - - 0.275 - - - - - - - nitric acid - - - - - - 0.55 - - - - - - maleic acid - - - - - - - 0.6 - - - - - fumaric acid - - - - - - - - 0.6 - - - - oxalic acid - - - - - - - - - 0.6 - - - methanesulfonic acid - - - - - - - - - - 0.6 - - Benzenesulfonic acid - - - - - - - - - - - 0.6 - toluenesulfonic acid - - - - - - - - - - - - 0.6

Example 43 44 45 46 47 48 49 50 51 52 53 54 55 Rivaroxaban (g) One One One One One One One One One One One One One Cationic polymer (g) PEI 3 3 3 3 3 3 3 3 3 3 3 3 3 acid (g) Hydrochloric acid - 0.275 - - - - - - - - - - - citric acid - - 0.6 - - - - - - - - - - hydrobromic acid - - - 0.875 - - - - - - - - - sulfuric acid - - - - 0.275 - - - - - - - - phosphoric acid - - - - - 0.275 - - - - - - - nitric acid - - - - - - 0.55 - - - - - - maleic acid - - - - - - - 0.6 - - - - - fumaric acid - - - - - - - - 0.6 - - - - oxalic acid - - - - - - - - - 0.6 - - - methanesulfonic acid - - - - - - - - - - 0.6 - - Benzenesulfonic acid - - - - - - - - - - - 0.6 - toluenesulfonic acid - - - - - - - - - - - - 0.6

Example 56 57 58 59 60 61 62 63 64 65 66 67 68 Rivaroxaban (g) One One One One One One One One One One One One One Cationic polymer (g) PLL 3 3 3 3 3 3 3 3 3 3 3 3 3 acid (g) Hydrochloric acid - 0.275 - - - - - - - - - - - citric acid - - 0.6 - - - - - - - - - - hydrobromic acid - - - 0.875 - - - - - - - - - sulfuric acid - - - - 0.275 - - - - - - - - phosphoric acid - - - - - 0.275 - - - - - - - nitric acid - - - - - - 0.55 - - - - - - maleic acid - - - - - - - 0.6 - - - - - fumaric acid - - - - - - - - 0.6 - - - - oxalic acid - - - - - - - - - 0.6 - - - methanesulfonic acid - - - - - - - - - - 0.6 - - Benzenesulfonic acid - - - - - - - - - - - 0.6 - toluenesulfonic acid - - - - - - - - - - - - 0.6

Example 69: Rivaroxaban solid dispersion capsule formulation

According to the composition of Table 7 below, a capsule was prepared using a rivaroxaban solid dispersion. After preparing a rivaroxaban solid dispersion powder in the same composition and manufacturing method as in Example 3, it was mixed with microcrystalline cellulose as a diluent, and the mixture was filled in gelatin capsules (No. 000).

Example 69 Weight (g) solid dispersion powder Rivaroxaban One AEA 3 citric acid 0.6 diluent Microcrystalline Cellulose 13.8

Example 70: Rivaroxaban solid dispersion tablet formulation

According to the composition of Table 8 below, granules containing rivaroxaban solid dispersion were prepared using a fluidized bed granulation method, and then tablets were prepared by tableting them.

Rivaroxaban according to the composition of Example 3, AEA as a hydrophilic polymer, and citric acid as an acid were completely dissolved in a mixed solvent of dichloromethane (80 parts by weight compared to rivaroxaban) and ethanol (20 parts by weight compared to rivaroxaban) Then, talc was suspended as a fluidizing agent to prepare a granulation solution. Separately, microcrystalline cellulose, lactose hydrate and colloidal silicon dioxide are put in a fluid bed granulator (Fluid Bed; supply air temperature 60 ± 10 ℃, spray rate 30 ± 10 mL/min) as a solid phase and flowed, and the granulation solution is sprayed to produce granules. did. Thereafter, croscarmellose sodium and crospovidone as a disintegrant and magnesium stearate as a lubricant were mixed in the prepared granules, and tableted and coated to prepare a tablet formulation.

Example 70 Weight (g) Rivaroxaban One Polyvinylacetaldiethylaminoacetic acid 3 citric acid 0.6 talc 0.185 Mixture of microcrystalline cellulose and lactose hydrate 1.3 Colloidal Silicon Dioxide (Aeroperl® 300) One Croscarmellose sodium (Primellose®) 2 crospovidone 2 magnesium stearate 0.05 Opadry 03B665001 Brown 4.5

Example 71: Rivaroxaban coated spherical granules

According to the composition of Table 9 below, rivaroxaban-coated spherical granules were prepared. Rivaroxaban according to the composition of Example 3, AEA as a hydrophilic polymer, and citric acid as an acid were completely dissolved in a mixed solvent of dichloromethane (80 parts by weight compared to rivaroxaban) and ethanol (20 parts by weight compared to rivaroxaban) Then, a coating solution was prepared by suspending talc as a fluidizing agent. Separately, microcrystalline cellulose spherical granules as a solid phase were put into a fluidized bed granulator (Fluid Bed; supply air temperature 60 ± 10 ℃, spray rate 30 ± 10 mL/min), flowed, and the coating solution was sprayed to coat the rivaroxaban solid dispersion. In this process, the spray speed and supply air temperature of the coating solution were appropriately adjusted so that the microcrystalline cellulose spherical granules were not agglomerated by the coating solution.

Example 71 Weight (g) Rivaroxaban One Polyvinylacetaldiethylaminoacetic acid 3 citric acid 0.6 talc 0.185 Microcrystalline Cellulose Spherical Granules 4.6

Example 72: Rivaroxaban-coated film-coated tablet

According to the composition of Table 10 below, rivaroxaban-coated film-coated tablets were prepared. Rivaroxaban according to the composition of Example 3, AEA as a hydrophilic polymer, and citric acid as an acid were completely dissolved in a mixed solvent of dichloromethane (80 parts by weight compared to rivaroxaban) and ethanol (20 parts by weight compared to rivaroxaban) Then, a coating solution was prepared by suspending talc as a fluidizing agent. Separately, the powder was mixed according to the composition shown in Table 11 below, and then compressed to a mass of 70 mg with a circular punch having a diameter of 3 mm to prepare a core tablet.

Put the core tablet in a pan coater that does not form a fluidized bed (Coater; supply air temperature 60 ± 10 ℃, spray rate 30 ± 10 mL/min), rotate and spray the coating solution to coat the rivaroxaban solid dispersion on the tablet surface. . In this process, the injection speed of the coating solution and the supply air temperature were appropriately adjusted so that the core tablets were not agglomerated by the coating solution to form defective products.

coating solution Weight (mg) Rivaroxaban 20.0 Polyvinylacetaldiethylaminoacetic acid 60.0 citric acid 12.0 talc 3.7

Core tablet composition weight% Silica Microcrystalline Cellulose 95% Croscarmellose Sodium 4 % magnesium stearate One %

Example 73: Rivaroxaban-coated film-coated tablet

According to the composition of Table 12 below, rivaroxaban-coated film-coated tablets were prepared. Rivaroxaban according to the composition of Example 3, AEA as a hydrophilic polymer, and citric acid as an acid were completely dissolved in a mixed solvent of dichloromethane (80 parts by weight compared to rivaroxaban) and ethanol (20 parts by weight compared to rivaroxaban) Then, a coating solution was prepared by suspending talc as a fluidizing agent. Separately, the powder was mixed according to the composition shown in Table 13 below, and then tableted to a mass of 70 mg with a circular punch having a diameter of 3 mm to prepare a core tablet.

The core tablet was put into a fluid bed coater (Fluid bed coater; supply air temperature 60 ± 10 °C, spray rate 30 ± 10 mL/min), flowed, and the coating solution was sprayed to coat the rivaroxaban solid dispersion on the tablet surface. In this process, the injection speed and supply air temperature of the coating solution were appropriately adjusted so that the core tablets were not agglomerated by the coating solution to form defective products.

coating solution Weight (mg) Rivaroxaban 20.0 Polyvinylacetaldiethylaminoacetic acid 60.0 citric acid 12.0 talc 3.7

Core tablet composition weight% Silica Microcrystalline Cellulose 95% Croscarmellose Sodium 4 % magnesium stearate One %

Experimental Example 1: Dissolution test of a solid dispersion containing rivaroxaban according to the composition ratio

For the powders of Examples 1 to 68 and Comparative Example 1, the dissolution profiles were compared by dissolution at 37.0 ± 0.5 ° C and 150 rpm in 300 mL of pH 4.5 eluate by the USP paddle method in Tables 14 to 18 and Figures 1 and 2 are shown.

Dissolution rate (%) time (minutes) 5 10 15 30 60 120 180 240 Example 1 37.7 45.1 47.2 45.3 44.3 43.7 42.8 43.8 Example 2 14.3 21.4 27.5 47.1 54.1 53.5 53.6 53.3 Example 3 41.3 47.3 48.2 54.8 59.2 60.3 57.2 57.2 Example 4 20.2 35.9 42.3 50.7 52.3 52.8 52.5 53.0 Example 5 29.4 31.5 35.6 40.9 42.6 42.7 42.3 42.6 Example 6 32.1 35.5 37.5 46.0 45.6 45.8 45.4 45.7 Example 7 16.3 23.5 29.7 37.8 49.8 48.6 49.5 49.1 Example 8 25.5 32.7 38.4 49.5 50.7 50.2 50.4 50.8 Example 9 22.4 27.8 35.9 40.8 44.8 45.1 44.6 45.0 Example 10 18.1 26.4 29.5 37.8 40.7 40.6 40.1 40.2 Example 11 11.0 15.8 20.7 35.9 42.6 42.5 42.1 42.3 Example 12 21.2 26.5 28.9 35.1 38.1 39.5 39.1 39.0 Example 13 19.5 23.1 28.4 32.1 41.1 41.5 41.3 41.4 Comparative Example 1 4.0 6.8 7.9 8.8 9.5 9.8 9.9 10.0

Dissolution rate (%) time (minutes) 5 10 15 30 60 120 180 240 Example 17 29.1 30.5 30.8 28.2 25.4 21.1 21.5 21.3 Example 18 45.4 49.3 44.1 35.7 32.2 27.5 26.3 26.3 Example 19 43.9 48.8 47.8 39.8 32.0 26.6 25.7 25.0 Example 20 44.3 47.5 46.5 36.4 33.1 24.5 24.9 24.7 Example 21 45.2 48.4 43.1 35.0 32.7 26.1 26.7 26.4 Example 22 46.1 49.4 42.0 32.8 29.5 22.1 22.5 22.9 Example 23 44.5 46.8 43.7 36.8 31.0 25.5 25.4 25.1 Example 24 42.8 47.2 41.8 34.5 29.7 24.9 24.6 24.5 Example 25 43.4 46.5 40.0 35.2 30.7 25.4 25.9 25.6 Example 26 43.2 48.3 42.6 35.5 31.8 26.1 26.4 26.3 Example 27 44.2 47.3 43.0 36.1 32.4 24.9 24.7 24.8 Example 28 45.1 46.2 42.8 32.1 28.9 24.0 24.6 24.3 Example 29 43.7 47.0 41.6 36.7 27.4 25.4 25.6 25.1 Comparative Example 1 4.0 6.8 7.9 8.8 9.5 9.8 9.9 10.0

Dissolution rate (%) time (minutes) 5 10 15 30 60 120 180 240 Example 30 11.6 15.8 25.6 38.5 42.1 40.3 38.1 35.7 Example 31 15.1 24.7 32.4 42.5 47.6 45.9 43.4 38.5 Example 32 13.5 24.1 30.8 41.0 44.5 41.3 40.3 37.1 Example 33 12.9 22.3 31.5 43.4 45.6 43.1 41.8 37.6 Example 34 13.8 25.1 33.4 42.9 45.8 41.6 40.7 35.4 Example 35 14.6 23.0 29.4 40.5 43.1 45.4 42.8 36.9 Example 36 13.8 26.4 32.1 42.5 44.8 45.8 41.5 36.1 Example 37 14.5 24.4 33.8 41.6 43.9 45.5 42.4 37.4 Example 38 13.5 23.8 29.7 41.5 44.2 45.2 43.1 36.5 Example 39 14.3 23.5 30.5 42.0 43.8 44.4 42.1 35.1 Example 40 12.7 22.8 29.4 40.9 43.4 44.5 41.6 35.4 Example 41 13.3 24.1 28.5 40.1 42.7 43.1 41.0 35.5 Example 42 12.6 22.4 30.6 39.5 41.6 42.1 40.5 36.0 Comparative Example 1 4.0 6.8 7.9 8.8 9.5 9.8 9.9 10.0

Dissolution rate (%) time (minutes) 5 10 15 30 60 120 180 240 Example 43 20.1 27.3 30.5 35.0 36.8 35.7 32.6 30.4 Example 44 32.2 34.8 37.2 40.8 43.0 41.8 37.5 32.9 Example 45 30.1 32.5 34.6 39.1 42.7 37.6 35.4 33.2 Example 46 32.6 35.6 37.1 42.1 44.6 40.9 38.4 32.4 Example 47 29.4 33.5 36.7 40.2 43.7 39.5 36.8 31.8 Example 48 33.5 36.1 38.4 41.5 42.4 40.1 34.7 30.5 Example 49 28.4 31.9 35.4 37.6 40.2 42.0 36.5 32.1 Example 50 25.6 29.4 32.7 35.6 38.4 39.3 37.5 29.4 Example 51 27.3 30.1 35.4 36.5 36.4 35.0 32.7 31.0 Example 52 29.4 32.4 34.7 36.4 37.7 34.2 33.1 30.7 Example 53 30.0 33.8 35.6 36.1 38.3 34.5 33.1 31.5 Example 54 29.7 31.5 32.6 37.0 38.6 35.6 34.2 32.0 Example 55 26.8 28.9 33.5 34.7 37.0 38.2 35.1 31.3 Comparative Example 1 4.0 6.8 7.9 8.8 9.5 9.8 9.9 10.0

Dissolution rate (%) time (minutes) 5 10 15 30 60 120 180 240 Example 56 18.5 25.4 32.0 34.2 36.5 36.0 35.7 35.5 Example 57 20.6 28.1 32.5 36.8 36.8 35.7 36.2 36.7 Example 58 17.2 22.1 27.6 31.5 35.1 35.8 35.4 35.3 Example 59 20.2 25.7 30.4 33.8 34.1 34.5 34.2 34.4 Example 60 27.6 33.4 34.8 35.9 37.8 37.2 37.5 37.4 Example 61 21.2 26.5 31.4 33.2 35.8 36.0 36.2 35.7 Example 62 25.0 27.2 30.6 32.1 34.5 35.2 35.0 35.1 Example 63 22.7 25.6 29.7 33.6 35.6 35.2 35.4 35.3 Example 64 21.8 24.6 30.1 32.5 33.9 33.7 33.4 33.8 Example 65 23.5 28.3 31.7 34.0 35.7 35.4 35.2 35.4 Example 66 19.1 25.4 28.6 33.1 34.6 34.4 34.2 34.6 Example 67 20.7 23.7 29.4 33.0 33.5 33.6 33.4 33.7 Example 68 19.5 23.8 28.9 31.2 34.2 33.9 34.0 34.1 Comparative Example 1 4.0 6.8 7.9 8.8 9.5 9.8 9.9 10.0

As shown in Tables 14 to 18 and FIGS. 1 and 2, Examples 1 to 68, which are rivaroxaban solid dispersions according to the present invention, had an elution concentration of about 2 to 5 times higher than that of Comparative Example 1. In particular, the solid dispersion prepared using AEA as the cationic polymer and citric acid as the acid showed the highest elution concentration. Since this increase in the elution concentration means that the solubility of rivaroxaban is increased, it can be clearly seen that the solubility of the rivaroxaban solid dispersion according to the present invention is increased.

Experimental Example 2: Evaluation of crystal change of rivaroxaban solid dispersion

Crystalline analysis (XRD) was performed through a powder X-ray diffraction pattern (XPRD) for the solid dispersion (Example 3) containing rivaroxaban according to the present invention, and it was confirmed that the rivaroxaban was changed from a crystalline form to an amorphous form. . The results are shown in FIG. 3 .

As confirmed in FIG. 3, in the case of rivaroxaban (Comparative Example 1) used as a raw material, the powder X-ray diffraction pattern showed a peak at a specific 2θ (°), and it was found that it was a crystalline form.

However, the solid dispersion obtained in Example 3 showed a halo pattern in the powder X-ray diffraction pattern (XPRD), from which it was found that the rivaroxaban solid dispersion was amorphous.

Experimental Example 3: Comparison of dissolution of rivaroxaban solid dispersion tablet formulation

For each tablet of Example 70 and Comparative Example 2 and Comparative Example 3, the dissolution was compared in the eluate at pH 1.2 and pH 4.5 by the method of Experimental Example 1, and the results are shown in FIG. 4 .

As shown in FIG. 4, the tablet formulation (Example 70) prepared with the composition of the solid dispersion according to the present invention was prepared in Comparative Example 2 (control drug) and Comparative Example 3 (composition of Korean Patent No. 10-1535586; polymer; As a result, the elution concentration was increased by about 400% and more than 50% compared to the solid dispersion using PVPVA64).

Experimental Example 4: Stability evaluation through comparison of production of related substances

For each tablet of Example 70 and Comparative Example 2 and Comparative Example 3, the stability of rivaroxaban was evaluated after preparing a solid dispersion powder or tablet formulation, and related substances were generated through liquid chromatography compared to be. According to the relative relation time (RRT), it can be classified into 0.18 (IMP B), 0.30 (IMP H), 0.57 (IMP D), 0.85 (IMP G), and 0.88 (IMP A). The results are shown in Table 19 below.

related substances Comparative Example 2 Comparative Example 3 Example 70 IMP B (%) N.D. N.D. N.D. IMP H (%) 0.04 N.D. 0.01 IMP D (%) 0.03 0.01 N.D. IMP G (%) 0.03 0.02 0.02 IMP A (%) 0.04 0.01 N.D. Total related substances (%) 0.14 0.38 0.14

As shown in Table 19, the related substances of the formulation (Example 70) prepared with the composition of the solid dispersion according to the present invention are at the same level as Comparative Example 2 (control), and Comparative Example 3 (PVPVA64 as a polymer) It was confirmed to be 36% of the solid dispersion used). The above results suggest that the solid dispersion according to the present invention can be more usefully used as a pharmaceutical composition because the production amount of related substances is lower than Comparative Example 3 prepared by melt extrusion.

Experimental Example 5: Comparison of rivaroxaban pharmacokinetics in beagle dogs

Pharmacokinetic evaluation was performed on the tablets of Example 70 and Comparative Example 2. The tablets of Example 70 and Comparative Example 2 were administered to 6 male beagle dogs per group so that the dose of rivaroxaban was 20 mg, the drug was administered, and blood was collected at predetermined time intervals. The pharmacokinetic profile was confirmed by analyzing the plasma concentration of rivaroxaban. The results are shown in Table 20 and FIG. 5 below.

AUC _0-12 (ng.hr/mL) C _max (ng/mL) Example 70 2850.1 765.0 Comparative Example 2 657.0 194.1

As shown in Table 20 and Figure 5, the tablets (Example 70) prepared using the rivaroxaban-containing solid dispersion according to the present invention had AUC and Cmax of 3.94 and 3.94, respectively, compared to the control drug (Comparative Example 2). It was confirmed that the increase was about 4.3 times. According to the above results, it can be seen that the rivaroxaban-containing composition according to the present invention has improved solubility and dissolution concentration of rivaroxaban, thereby maximizing the drug concentration in a specific organ to increase bioavailability and maximizing the effect of the drug. can

From the above description, those skilled in the art to which the present invention pertains will understand that the present invention may be embodied in other specific forms without changing the technical spirit or essential characteristics thereof. In this regard, it should be understood that the embodiments described above are illustrative in all respects and not restrictive. The scope of the present invention should be construed as being included in the scope of the present invention, rather than the above detailed description, all changes or modifications derived from the meaning and scope of the claims described below and their equivalents.

The rivaroxaban solid dispersion according to the present invention can significantly improve the solubility of rivaroxaban, which is poorly soluble, and the formulation prepared using the rivaroxaban solid dispersion secures sufficient safety and at the same time has remarkably excellent dissolution and biologic properties. By indicating the utilization rate, the therapeutic effect can be maximized.

Claims (26)

(a) preparing a solution comprising a solvent, rivaroxaban, a pharmaceutically acceptable cationic polymer and an acid; and
(b) converting said solution into a pharmaceutical composition. delete The method of claim 1, wherein the step of converting the solution into a pharmaceutical composition comprises the step of preparing a solid dispersion of rivaroxaban by spraying the solution. The method according to claim 3, wherein the solid dispersion is a powder or granules. 5. The method of claim 4, wherein the spraying of the solution is performed using a spray dryer or a fluidized bed granulator. According to claim 1, wherein the pharmaceutically acceptable cationic polymer is polyvinylacetaldiethylaminoacetic acid (AEA), dimethylaminoethyl methacrylate-methyl methacrylate copolymer (Eudragit E), chitosan (CS), polyethyleneimine (PEI) and poly-L-lysine (PLL) at least any one selected from the group consisting of, a method for producing a pharmaceutical composition for oral use. According to claim 1, wherein the acid is any one selected from the group consisting of hydrochloric acid, citric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, maleic acid, fumaric acid, tartaric acid, malic acid, oxalic acid, methanesulfonic acid, benzenesulfonic acid and toluenesulfonic acid The above method for preparing an oral pharmaceutical composition. The method of claim 1, wherein the solvent is at least one selected from the group consisting of water, methanol, ethanol, isopropanol, acetone, acetonitrile, dichloromethane and tetrahydrofuran. The method according to claim 1, wherein the solvent is a mixed solvent of dichloromethane and ethanol. The method according to claim 1, wherein the solvent is in a ratio by weight of dichloromethane and ethanol of 9: 1 to 1: 9. The method of claim 1 , wherein the pharmaceutical composition further comprises a pharmaceutically acceptable additive. The method of claim 11, wherein the pharmaceutically acceptable additive is a diluent, a binder, an excipient, a disintegrant, a lubricant, or a mixture thereof. The method according to claim 1, wherein the pharmaceutical composition is a solid dispersion, granule, powder, capsule, tablet, spherical granule or film-coated tablet. (a) preparing a solution comprising a solvent, rivaroxaban and a pharmaceutically acceptable cationic polymer; and
(b) converting said solution into a pharmaceutical composition, comprising the steps of:
The step (a) is a step of preparing a coating solution by dissolving rivaroxaban, polyvinylacetaldiethylaminoacetic acid (AEA) and citric acid in a mixed solution in which the ratio by weight of dichloromethane and ethanol is 4:1; and
The step (b) is a method for preparing a film-coated tablet by putting the core tablet into a pan coater and spraying the coating solution. 15. An oral pharmaceutical composition prepared by the method of any one of claims 1 and 3 to 14. The method according to claim 15, wherein the composition uses 300 mL of an eluate having a pH of 4.5 as a dissolution medium and under the dissolution test conditions in which the paddle is rotated at 150 rpm, the release concentration of rivaroxaban is 4 hours after the start of the test. It is improved by more than 2 times compared to the savannah fine particles, and the dissolution concentration is maintained, an oral pharmaceutical composition. 16. The oral pharmaceutical composition of claim 15, wherein the composition comprises amorphous rivaroxaban. An oral pharmaceutical composition comprising rivaroxaban, a pharmaceutically acceptable cationic polymer and an acid, wherein the acid is hydrochloric acid, citric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, maleic acid, tartaric acid, malic acid, oxalic acid, methanesul Any one or more selected from the group consisting of phonic acid, benzenesulfonic acid and toluenesulfonic acid, an oral pharmaceutical composition. The method of claim 18, wherein the pharmaceutically acceptable cationic polymer is polyvinylacetaldiethylaminoacetic acid (AEA), dimethylaminoethyl methacrylate-methyl methacrylate copolymer (Eudragit E), chitosan (CS), polyethyleneimine (PEI) and poly-L-lysine (PLL) any one or more selected from the group consisting of, oral pharmaceutical composition. delete delete 19. The oral pharmaceutical composition of claim 18, wherein the pharmaceutical composition further comprises a pharmaceutically acceptable additive. The oral pharmaceutical composition of claim 22, wherein the pharmaceutically acceptable additive is a diluent, binder, excipient, disintegrant, lubricant, or mixture thereof. The oral pharmaceutical composition according to claim 18, wherein the pharmaceutical composition is a solid dispersion, granule, powder, capsule, tablet, spherical granule or film-coated tablet. 19. The method of claim 18, wherein the composition uses 300 mL of an eluate having a pH of 4.5 as a dissolution medium and under the dissolution test conditions in which the paddle is rotated at 150 rpm, the release concentration of rivaroxaban is 4 hours after the start of the test. It is improved by more than 2 times compared to savannah fine particles, and the dissolution concentration is maintained, an oral pharmaceutical composition. 19. The oral pharmaceutical composition of claim 18, wherein the composition comprises amorphous rivaroxaban.

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