KR102222774B1 - Pharmaceutical formulation comprising edoxaban and preparation method thereof - Google Patents

Abstract

The present invention relates to a preparation containing edoxaban as an active ingredient and a method for preparing the same. The formulation containing edoxaban as an active ingredient of the present invention exhibits an excellent dissolution pattern, has excellent bioavailability, and considerably reduces the time and cost in manufacturing the formulation through the low viscosity of the coating agent, thereby reducing the formulation itself and its manufacturing method. Shows an excellent effect.

Description

Pharmaceutical formulation containing edoxaban and its manufacturing method {PHARMACEUTICAL FORMULATION COMPRISING EDOXABAN AND PREPARATION METHOD THEREOF}

The present invention relates to a preparation containing edoxaban as an active ingredient and a method for preparing the same.

Edoxaban is a compound useful as a prophylactic and/or therapeutic agent for thrombotic diseases by inhibiting activated blood coagulation factor X (also referred to as activating factor X or FXa), and N ¹ -(5-chloropyridine- represented by the following formula 1) 2-yl)-N ² -((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5 ,4-c]pyridin-2-yl)carbonyl]aminocyclohexyl)ethandiamide.

[Formula 1]

Edoxaban is commercialized in the form of p-toluenesulfonate·1·hydrate represented by the following formula (2) and is sold as lixiana.

[Formula 2]

Although the compound of Formula 1 exhibits good solubility in a strongly acidic aqueous solution, it is well known that solubility decreases in an aqueous solution in a neutral region (eg, a neutral buffer solution). Accordingly, in order to solve this problem, there have been many researches and developments on the formulation of edoxaban, but sufficient effects have not been achieved.

In addition, various methods currently known have a large disadvantage in manufacturing efficiency and manufacturing cost by taking a considerable amount of time in the manufacturing process.

Under this background, the present inventors completed the present invention by developing a novel formulation containing edoxaban as an active ingredient and a method for preparing the same.

Korean Patent Publication No. 10-2018-0022125

The present invention is a compound represented by the following formula (1), or a pharmaceutically acceptable salt or hydrate thereof; And it provides a formulation containing pea starch as a coating agent.

[Formula 1]

The present invention provides a method for preparing a formulation comprising the step of coating the compound represented by Formula 1, or a pharmaceutically acceptable salt or hydrate thereof, with pea starch.

Hereinafter, the present invention will be described in more detail.

The present invention is a compound represented by the following formula (1), or a pharmaceutically acceptable salt or hydrate thereof; And it provides a formulation containing pea starch as a coating agent.

[Formula 1]

The compound represented by Formula 1 is N ¹ -(5-chloropyridin-2-yl)-N ² -((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-[(5 Named as -methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]aminocyclohexyl)ethanidiamide and called edoxaban.

In the present invention, the pharmaceutically acceptable salt is physiologically acceptable and when administered to a human, it does not usually cause allergic reactions such as gastrointestinal disorders, dizziness, or similar reactions, and self-medicine formulations having ordinary knowledge in the field. It may mean that it is commonly used during manufacture.

Such pharmaceutically acceptable salts may refer to salts formed with inorganic or organic acids or bases.

Specifically, it may be any one selected from the group consisting of tartrate, hydrochloride, citrate, malate, phosphate, sulfate, malonic acid, oxalate, bromate, and tosylate.

In the present invention, the "hydrate" may include a stoichiometric amount of water, in which water is bound by a non-covalent intermolecular force, such as edoxaban or a pharmaceutically acceptable salt thereof, and the like. Specifically, the hydrate may contain water in a ratio of about 0.25 mol to about 10 mol based on 1 mol of the active ingredient, and more specifically, about 0.5 mol, about 1 mol, about 1.5 mol, about 2 mol, about It may include 2.5 moles, about 3 moles, about 5 moles, and the like. Preferably, the hydrate may be a monohydrate of edoxaban citric acid salt.

In the present invention, pea starch means starch derived from peas. This is a starch with an amylose content of at least about 50% by weight of the starch. Pea starch is an unmodified pea starch as well as a modified functional group (e.g., hydroxyl group) of the starch (e.g., substituted with a C2-C8 hydroxy alkyl group, e.g., hydroxy propyl or hydroxy ethyl group. ) Contains both pea starch. A preferred example of such modified pea starch is pregelatinized hydroxypropyl pea starch. Pregelatinized hydroxypropyl pea starch contains, for example, 2-7% of hydroxypropyl groups. Examples of such modified pea starches and the like Lai coat (Lycoat ^®). Specifically, Lycoat ^® RS780, Lycoat ^® RS720 and the like.

In the present invention, the formulation uses pea starch as a coating agent. The formulation of the present invention is excellent in bioavailability by showing an excellent dissolution pattern by using pea starch as a coating agent. In particular, it has the advantage of showing a similar dissolution pattern compared to a commercially available drug, and significantly reduces time and cost in manufacturing a formulation through its low viscosity.

The formulation of the present invention is preferably a tablet.

The tablet according to the present invention may be prepared by wet granulation, direct tableting or dry granulation, and preferably by wet granulation or direct tableting.

In the formulation, the compound represented by Formula 1 is included in an amount of 7 to 30% by weight, preferably 10 to 25% by weight, based on the total weight of the formulation.

In the formulation, a coating agent containing pea starch is included in an amount of 1 to 7% by weight, preferably 1.5 to 5% by weight, based on the total weight of the formulation.

The formulation of the present invention may contain any one or more excipients selected from the group consisting of mannitol, erythritol, xylitol, pregelatinized starch and crystalline cellulose as excipients. Preferably the excipients are mannitol and pregelatinized starch. Mannitol and pregelatinized starch are excipients that can help in dissolution by improving the solubility of the compound of formula (1). In the formulation, the excipient is included in an amount of 40 to 80% by weight, preferably 50 to 70% by weight, based on the total weight of the formulation.

The formulation of the present invention may include any one or more disintegrants selected from the group consisting of crospovidone, carmellose and sodium carboxymethyl starch as a disintegrant. Preferably the disintegrant is crospovidone. In the formulation, the disintegrant is contained in an amount of 1 to 10% by weight, preferably 2 to 8% by weight, based on the total weight of the formulation.

The formulation of the present invention may include any one or more binders selected from the group consisting of hydroxypropylcellulose, hydroxypropylmethylcellulose, povidone and vinylpyrrolidone as a binder. Preferably the binder is hydroxypropylcellulose. In the formulation, the binder is included in an amount of 3 to 15% by weight, preferably 4 to 10% by weight, based on the total weight of the formulation.

The formulation of the present invention may include any one or more lubricants selected from the group consisting of talc, colloidal silicon dioxide, magnesium stearate, and sodium stearyl fumarate as a lubricant. Preferably the lubricant is talc and colloidal silicon dioxide. In the formulation, the lubricant is included in an amount of 3 to 15% by weight, preferably 4 to 10% by weight, based on the total weight of the formulation.

The formulation of the present invention may further contain sorbitol and propylene glycol in addition to pea starch as a coating agent. As a coating agent, pea starch is preferably contained in an amount of 50 to 70% by weight of the total coating agent content.

In addition, the present invention may further include a colorant, and may further include a commonly used colorant such as titanium oxide and yellow iron oxide.

The formulation of the present invention is preferably a compound represented by Formula 1, or a pharmaceutically acceptable salt or hydrate thereof;

Any one or more excipients selected from the group consisting of mannitol, erythritol, xylitol, pregelatinized starch and crystalline cellulose;

Any one or more binders selected from the group consisting of hydroxypropylcellulose, hydroxypropylmethylcellulose, povidone and vinylpyrrolidone;

Any one or more lubricants selected from the group consisting of talc, colloidal silicon dioxide, magnesium stearate, and sodium stearyl fumarate;

Any one or more disintegrants selected from the group consisting of crospovidone, carmellose and sodium carboxymethyl starch; And

It includes a coating agent that is pea starch.

More preferably, the formulation of the present invention is a compound represented by Formula 1, or a pharmaceutically acceptable salt or hydrate thereof;

Excipients of mannitol and pregelatinized starch;

A binder of hydroxypropylcellulose;

Lubricants of talc and colloidal silicon dioxide;

Disintegrants of crospovidone; And

It provides a formulation comprising a coating agent that is pea starch.

The present invention provides a method for preparing a formulation comprising the step of coating the compound represented by Formula 1, or a pharmaceutically acceptable salt or hydrate thereof, with pea starch.

The formulation according to the invention is preferably a tablet and can be prepared by wet granulation, dry granulation or direct tableting. More preferably, it may be prepared by wet granulation or direct tableting.

The preparation method of the formulation is preferably

(a) mixing the compound represented by Formula 1, or a pharmaceutically acceptable salt thereof, with an excipient, a binder, a disintegrant, and a lubricant;

(b) preparing uncoated tablets from the mixture; And

(c) coating the uncoated tablet with pea starch.

In the above preparation method, excipients, binders, disintegrants, and lubricants are the same as those of salpin in the formulation.

Steps (a) and (b) may be performed by wet granulation or direct tableting, appropriately modified at a level generally applicable.

In the step (a), it preferably contains more than 10% of moisture. By including moisture in excess of 10%, granules are produced in a large size in the mixing process, thereby improving the flowability of the mixture.

The coating of step (c) may further include sorbitol and propylene glycol as a coating agent in addition to pea starch.

By using the pea starch, the coating can be quickly performed in a short time by providing a low viscosity of the coating agent.

The preparation method of the preparation according to the present invention provides a preparation having an excellent dissolution rate, and significantly reduces time and cost in preparation of the preparation, thereby exhibiting excellent effects in terms of the preparation and its preparation method.

The present invention relates to a compound represented by Chemical Formula 1, or a pharmaceutically acceptable salt or hydrate thereof; And it provides a pharmaceutical composition comprising a formulation containing pea starch as a coating.

The above pharmaceutical composition is useful as a blood coagulation agent, as a prophylactic and/or therapeutic agent for blood clotting agents, blood clots or embolisms, because it exhibits a high activated blood coagulant factor X (FXa) inhibitory action. The pharmaceutical composition of the present invention is a medicament for mammals including humans, an activated blood coagulant factor X inhibitor, a blood coagulation inhibitor, a prophylactic and/or therapeutic agent for thrombus and/or embolism, a prophylactic and/or therapeutic agent for thrombotic diseases, Furthermore, cerebral infarction, cerebral embolism, pulmonary infarction, pulmonary embolism, myocardial infarction, angina pectoris, thrombosis and/or embolism associated with non-membranous atrial cells (NVAF), deep vein thrombosis, deep vein thrombosis after surgical operation, artificial bowel/joint replacement Thromboembolism after total hip arthroplasty (THR), thromboembolism after total knee arthroplasty (TKR), thromboembolism after hip fracture surgery (HFS), thrombus formation and/or reocclusion after blood circulation reconstruction, Burger's disease, widespread Intravascular coagulation syndrome, systemic inflammatory response syndrome (SIRS), multiple organ failure (MODS), blood clot formation during extracorporeal circulation or blood clotting during blood collection are useful as a preventive and/or therapeutic agent.

The present invention relates to a compound represented by Chemical Formula 1, or a pharmaceutically acceptable salt or hydrate thereof; And it provides a method of treating a thrombotic disease by administering a pharmaceutical composition comprising a formulation containing pea starch as a coating agent in a therapeutically effective amount.

Matters mentioned in the formulation of the present invention can be equally applied to pharmaceutical compositions, treatment methods, and therapeutic uses as long as they do not contradict each other.

The formulation containing edoxaban as an active ingredient of the present invention exhibits an excellent dissolution pattern, has excellent bioavailability, and considerably reduces the time and cost in manufacturing the formulation through the low viscosity of the coating agent, thereby significantly reducing the properties of the formulation itself and its manufacturing method. It shows an excellent effect from the side.

Hereinafter, examples will be described in detail to aid understanding of the present invention. However, the following examples are merely illustrative of the contents of the present invention, and the scope of the present invention is not limited to the following examples. The embodiments of the present invention are provided to more completely describe the present invention to those of ordinary skill in the art.

Example One. Edoxaban Citrate Monohydrate Inclusion tablet manufacturing

After mixing 153.79 g of D-mannitol, 84.00 g of pregelatinized starch, 4.00 g of crospovidone, 28.00 g of hydroxypropylcellulose, and 83.01 g of edoxaban citrate monohydrate, HSM ( High Speed Mixer). HSM (SM-5C, Sejong Pharmatech) was used for wet granulation. The granulated material was dried with a fluid bed dryer. Fluid bed dryer (GPCG-1, Glatt GmbH) was used as the fluid bed dryer. The dried granulated material was sized with a sizing machine. Comil (197, Quadro) was used as a sizing machine. After adding 16.00 g of crospovidone to 352.80 g of sized product, 28.00 g of talc and 3.20 g of colloidal silicon dioxide are added and mixed. The final mixture was tableted using a single tablet press (EK-0, Korsch) and a rotary tablet press (GRC-7S, Sejong Pharmatech).

In 67.80 mL of purified water, 6.84 g of pregelatinized hydroxypropyl pea starch, 2.16 g of D-sorbitol, 0.96 g of propylene glycol 6000, 1.80 g of titanium oxide and 0.24 g of yellow iron oxide were added to a homogenizer (Ultra-turrax T 50, IKA) to prepare a suspension and then stir. The tablets were put in a coater (LCM, O'HARA) and film-coated with a 15 w/w% suspension to a coating amount of 12 mg/tablet.

The specific composition thereof is shown in Table 1 below.

[Table 1] Composition of tablets containing edoxaban citrate monohydrate

Example 2 to 11. Edoxaban Inclusion tablet manufacturing

Tablets were prepared for edoxaban in Table 2 below, or a pharmaceutically acceptable salt or hydrate thereof.

[Table 2] Edoxaban, or a pharmaceutically acceptable salt or hydrate thereof

[Table 3] Tablet composition

D-mannitol as shown in Table 3; Pregelatinized starch; Some crospovidone; Hydroxypropyl cellulose; And edoxaban, or a pharmaceutically acceptable salt or hydrate thereof, were mixed, and then granulated with a High Speed Mixer (HSM) using purified water. Purified water was used in excess of 10% of the total weight in the granulation process of each of the above edoxaban. HSM (SM-5C, Sejong Pharmatech) was used for wet granulation. The granulated material was dried with a fluid bed dryer. Fluid bed dryer (GPCG-1, Glatt GmbH) was used as the fluid bed dryer. The dried granulated material was sized with a sizing machine. Comil (197, Quadro) was used as a sizing machine. Add the remaining crospovidone to the sized product and mix, then add talc and colloidal silicon dioxide and mix. The final mixture was tableted using a single-shot tablet press (EK-O, Korsch) and a rotary tablet press (GRC-7S, Sejong Pharmatech). Pregelatinized hydroxypropyl pea starch, D-sorbitol, propylene glycol 6000, titanium oxide and yellow iron oxide were added to purified water, and a suspension was prepared with a homogenizer (Ultra-turrax T 50, IKA), followed by stirring. The tablets were put in a coating machine (LCM, O'HARA) and film-coated with a coating suspension of 12 mg/tablet.

Example 12 to 22. Edoxaban Inclusion tablet manufacturing

D-mannitol, pregelatinized starch, crospovidone, hydroxypropyl cellulose and edoxaban, or pharmaceutically acceptable salts or hydrates thereof were mixed as shown in Tables 1 and 3, and then talc and colloidal silicon dioxide were added. Mixed. The final mixture was tableted using a single tablet press (EK-0, Korsch) and a rotary tablet press (GRC-7S, Sejong Pharmatech). Pregelatinized hydroxypropyl pea starch, D-sorbitol, propylene glycol 6000, titanium oxide and yellow iron oxide were added to purified water, and a suspension was prepared with a homogenizer (Ultra-turrax T 50, IKA), followed by stirring. The tablets were put in a coater (LCM, O'HARA) and film-coated with a coating suspension of 12 mg/tablet.

Comparative example 1 and 2. Edoxaban Tosylate Monohydrate Inclusion tablet manufacturing

Tablets were prepared in the composition of Tables 4 and 5 below based on the formulation examples described in the examples of Korean Patent Registration No. 10-1424843.

Table 4 Edoxaban 30 mg tablets (Comparative Example 1)

Table 5 Edoxaban 60 mg tablets (Comparative Example 2)

Experimental Example 1. Confirmation of reduction of coating time

In the manufacturing process of the formulation of Example 1 and the formulation of Comparative Example 2 above, the time taken from the uncoated tablet to the completion of the coating was compared.

According to Example 1 using pregelatinized hydroxypropyl pea starch (LYCOAT ^® ), it took about 32 minutes to complete the coating with 3% by weight of the total weight of the tablet in the uncoated state.

On the other hand, in the case of the preparation of the coated tablet of the formulation of Comparative Example 2, it was confirmed that it took about 72 minutes to take about 40 minutes or more. Moreover, it was confirmed that the coated tablet of Comparative Example 2 required an additional drying time after coating, so that a considerably long time was required for tablet manufacturing. In addition, in the preparation of the coated tablet of Comparative Example 2, a bearding phenomenon occurred after coating the tablet due to the high viscosity of the coating agent. Accordingly, there was a problem in that the coating could not be immediately performed again and the cleaning operation of the device had to be performed, and the manufacturing process of the formulation was significantly delayed.

In other words, as compared to the method of the comparative example above, the present invention not only significantly shortens the coating time through the change of the coating agent, but also does not require an additional drying or device cleaning step required after manufacturing the coated tablet. It has an excellent advantage in the manufacturing process. Through this, it was confirmed that the cost and time efficiency in the manufacture of the formulation were significantly improved.

Experimental Example 2. Confirmation of dissolution rate

As the dissolution test solution, a pH 1.2 solution (the first solution of the KP 11 disintegration test method), a pH 4.0 solution, a pH 6.8 solution (the second solution of the KP 11 disintegration test method), and water are used in the second method of the KP 11 dissolution test (paddle). Method), a dissolution test was carried out at 50 rpm.

In the dissolution rate test, 60 mg of lixiana tablets were used as the formulation of Example 1 and commercially available edoxaban tablets.

For the pH 1.2 solution (the first solution of the KP 11 disintegration test method), the pH 4.0 solution, and the water, samples of the elution test solution were taken 5, 10 and 15 minutes after the start of the test, and 5, 10, 15, 30 only in the pH 6.8 solution. , Samples of the elution test solution were taken at 60 and 120 minutes. It was analyzed by liquid chromatography under the following conditions, and the results are shown in Tables 6 to 9.

<Liquid chromatography conditions>

-Column: A column filled with 5 μm octadecylsilyl silica gel for liquid chromatography in a stainless tube with an inner diameter of 4.6 mm and a length of 250 mm, or equivalent column (XTerra C18, 4.6 x 250 mm, 5 μm)

-Column temperature: 25 ℃

-Sample injection volume: 5 μL

-Mobile phase: Mobile phase A: Mobile phase B = 75: 25 (v/v)

* Mobile phase A: 0.1% trifluoroacetic acid

* Mobile phase B: acetonitrile

-Flow rate: 1.0 mL/min

-Detector: ultraviolet absorbance photometer (measurement wavelength 290 nm)

[Table 6] pH 1.2 dissolution test

[Table 7] pH 6.8 dissolution test

[Table 8] pH 4.0 dissolution test

[Table 9] Water dissolution test

As can be seen from the table above, it was confirmed that the formulation of Example 1 exhibited an almost similar dissolution phenomenon compared to the commercially available product.

That is, the present invention provides an excellent formulation by significantly shortening the manufacturing time and greatly reducing the cost required for the manufacturing process while exhibiting a dissolution rate equivalent to that of a commercially available formulation.

From the above description, those skilled in the art to which the present invention pertains will be able to understand that the present invention can be implemented in other specific forms without changing the technical spirit or essential features thereof. In this regard, it should be understood that the embodiments described above are illustrative in all respects and do not limit the invention. The scope of the present invention should be construed as including all changes or modified forms derived from the meaning and scope of the claims to be described later rather than the above detailed description and equivalent concepts thereof.

Claims (12)

A compound represented by the following formula (1), or a pharmaceutically acceptable salt or hydrate thereof; And a formulation containing pea starch as a coating agent
[Formula 1]

. The formulation of claim 1, wherein the formulation is a tablet. The method of claim 1, wherein the pharmaceutically acceptable salt of the compound represented by Formula 1 is a group consisting of tartrate, hydrochloride, citrate, malate, phosphate, sulfate, malonic acid salt, oxalate, bromate and tosylate. Any one formulation selected from. The formulation of claim 1, wherein the hydrate of the compound represented by Formula 1 is a monohydrate of the citrate of the compound represented by Formula 1. The formulation of claim 1, wherein the pea starch is pregelatinized hydroxypropyl pea starch. The method of claim 1, wherein the compound represented by Formula 1, or a pharmaceutically acceptable salt or hydrate thereof is 7 to 30% by weight based on the total weight of the formulation; And
A formulation comprising the coating agent in an amount of 1 to 7% by weight based on the total weight of the formulation. According to claim 1, wherein the formulation is any one or more excipients selected from the group consisting of mannitol, erythritol, xylitol, pregelatinized starch and crystalline cellulose;
Any one or more binders selected from the group consisting of hydroxypropylcellulose, hydroxypropylmethylcellulose, povidone and vinylpyrrolidone;
Any one or more lubricants selected from the group consisting of talc, colloidal silicon dioxide, magnesium stearate, and sodium stearyl fumarate;
The formulation further comprising any one or more disintegrants selected from the group consisting of crospovidone, carmellose and carboxy methyl starch sodium. A method for producing a formulation comprising the step of coating a compound represented by the following Formula 1, or a pharmaceutically acceptable salt or hydrate thereof, with pea starch.
[Formula 1]

. The method of claim 8, wherein the formulation is a tablet, and the formulation is prepared by wet granulation, dry granulation or direct tableting. The method of claim 8, wherein the preparation method is
(a) mixing the compound represented by Formula 1, or a pharmaceutically acceptable salt thereof, with an excipient, a binder, a disintegrant, and a lubricant;
(b) preparing uncoated tablets from the mixture; And
(c) coating the uncoated tablet with pea starch. The method of claim 10,
The (a) step is to contain more than 10% moisture when mixing, the method for producing a formulation. The method of claim 10,
The method of manufacturing a formulation that further comprises sorbitol and propylene glycol as a coating agent in step (c).