WO2020022824A1 - Pharmaceutical formulation comprising edoxaban and preparation method therefor - Google Patents

Abstract

The present invention relates to a formulation comprising edoxaban as an active ingredient and a preparation method therefor. The formulation comprising edoxaban as an active ingredient, according to the present invention, exhibits an excellent dissolution pattern, thus has excellent bioavailability, and, due to the low viscosity of a coating agent, allows a significant reduction in the time and costs required for the preparation of the formulation, thereby exhibiting excellent effects in the formulation itself and the preparation method therefor.

Description

Pharmaceutical formulations comprising Edoxaban and preparation method thereof

The present invention relates to a preparation comprising the edoxaban as an active ingredient and a preparation method thereof.

Edoxaban is a compound that inhibits activated blood coagulation factor X (also referred to as activation factor X or FXa) and is useful as a prophylactic and / or therapeutic drug for thrombotic diseases, wherein N ^1- (5-chloropyridine- 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) ethanediamide.

[Formula 1]

Edoxaban is commercialized in the form of p-toluenesulfonic acid salt, hydrate, represented by the following formula (2), and sold as lyciana.

[Formula 2]

It is well known that the compound of the formula (1) shows good solubility in a strongly acidic aqueous solution, but the solubility decreases in an aqueous solution in the neutral region (for example, a neutral buffer solution, etc.). Accordingly, there have been many research and developments on the formulation of Edoxaban to solve these problems, but did not achieve sufficient effects.

In addition, various currently known methods have significant disadvantages in manufacturing efficiency and manufacturing cost since they take considerable time in the manufacturing process.

Under this background, the present inventors have completed the present invention by developing a novel formulation containing Edoxaban as an active ingredient and a preparation method thereof.

[Preceding technical literature]

[Patent Documents]

(Patent Document 1) Republic of Korea 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 pea starch as a coating agent.

[Formula 1]

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

EMBODIMENT OF THE INVENTION Hereinafter, this invention is demonstrated in detail.

The present invention is a compound represented by the following formula (1), or a pharmaceutically acceptable salt or hydrate thereof; And 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 -Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] aminocyclohexyl) ethanediamide and is called edoxaban.

Pharmaceutically acceptable salts in the present invention, when physiologically acceptable and administered to a human, are usually self-pharmaceutical formulations having ordinary skill in the art without causing gastrointestinal disorders, allergic reactions such as dizziness or the like. It may mean that the conventional use in the 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 tartarate, hydrochloride, citrate, malate, phosphate, sulfate, malonate, oxalate, bromate and tosylate.

In the present invention, the 'hydrate' is that the doxaban or a pharmaceutically acceptable salt thereof and the like water is coupled to the non-covalent intermolecular force may include a stoichiometric amount of water. Specifically, the hydrate may include about 0.25 mol to about 10 mol of water based on 1 mol of the active ingredient, more specifically about 0.5 mol, about 1 mol, about 1.5 mol, about 2 mol, about 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 pea. This is starch having an amylose content of at least about 50% by weight of starch. Pea starch is a modified (eg, substituted with C2-C8 hydroxy alkyl group, eg, hydroxy propyl or hydroxy ethyl group, as well as unmodified pea starch, as well as functional groups (eg, hydroxyl groups) of the starch). ) 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 starch include Lycoat ^® and the like. Specifically, Lycoat ^® RS780, Lycoat ^® RS720 and the like.

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

The formulation of the present invention is preferably a tablet.

Tablets according to the invention can be prepared by wet granulation, direct tableting or dry granulation methods, preferably by wet granulation or direct tableting.

The formulation includes 7 to 30% by weight, preferably 10 to 25% by weight of the compound represented by Formula 1 based on the total weight of the preparation.

The formulation comprises 1 to 7% by weight, preferably 1.5 to 5% by weight, of a coating comprising pea starch, relative to the total weight of the formulation.

The formulations of the present invention may comprise 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 can be used as an excipient to improve the solubility of the compound of formula 1 to aid in dissolution. The formulation comprises 40 to 80% by weight, preferably 50 to 70% by weight, based on the total weight of the formulation.

The formulations of the present invention may comprise any one or more disintegrants selected from the group consisting of crospovidone, carmellose and carboxy methyl starch sodium as disintegrants. Preferably the disintegrant is crospovidone. The formulation comprises 1 to 10% by weight, preferably 2 to 8% by weight, of disintegrant, 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 hydroxypropyl cellulose, hydroxypropyl methyl cellulose, povidone and vinylpyrrolidone as binders. Preferably the binder is hydroxypropylcellulose. The formulation comprises from 3 to 15% by weight, preferably from 4 to 10% by weight, of the binder relative to 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 oxide, magnesium stearate, and sodium stearyl fumarate as lubricants. Preferably the lubricant is talc and colloidal silicon oxide. The formulation comprises 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 comprise sorbitol and propylene glycol in addition to pea starch as a coating. Pea starch as a coating agent is preferably included in 50 to 70% by weight of the total coating content.

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

The preparations of the present invention preferably comprise 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;

At least one binder selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methyl cellulose, povidone and vinylpyrrolidone;

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

Any one or more disintegrant selected from the group consisting of crospovidone, carmellose and carboxy methyl starch sodium; And

And a coating 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;

Binders of hydroxypropyl cellulose;

Glidants of talc and colloidal silicon oxide;

Disintegrants of crospovidone; And

Provided is a formulation comprising a coating that is pea starch.

The preparations according to the invention are preparations for use in the prevention or treatment of thrombotic diseases. For example, the thrombotic disease may be at least one selected from the group consisting of cerebral infarction, cerebral embolism, pulmonary infarction, pulmonary embolism, myocardial infarction, angina pectoris, thrombosis and embolism.

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

The preparations according to the invention are preferably tablets and can be prepared by wet granulation, dry granulation or direct tableting. More preferably by wet granulation or direct tableting methods.

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 with the mixture; And

(c) coating the uncoated tablets with pea starch.

Excipients, binders, disintegrants and glidants in the preparation method are as described above in the formulation.

Steps (a) and (b) may be performed by appropriate modification at a level that is normally applicable by wet granulation or direct tableting.

In the step (a) it preferably comprises more than 10% moisture. By including more than 10% of the moisture, the granules are largely prepared in the mixing process, thereby improving the flowability of the mixture.

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

By using the pea starch can provide a low viscosity of the coating agent to perform the coating quickly in a short time.

The process for the preparation of the preparations according to the invention exhibits an excellent effect in terms of preparations and methods for their preparation by providing preparations with good dissolution rates, while significantly reducing time and cost in the preparation of the preparations.

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

The pharmaceutical composition is useful as a prophylactic and / or therapeutic agent for blood coagulation preparations, blood clots or embolisms in that it exhibits a high activating blood coagulation factor X (FXa) inhibitory effect. The pharmaceutical composition of the present invention is a pharmaceutical, activated blood coagulant X factor inhibitor, a blood coagulation inhibitor, a thrombus and / or embolism prevention and / or treatment for mammals, including humans, and a prophylaxis and / or treatment of thrombotic disease, May include cerebral infarction, cerebral embolism, pulmonary infarction, pulmonary embolism, myocardial infarction, angina pectoris and / or embolism associated with non-membranous atrial cell (NVAF), deep vein thrombosis, deep vein thrombosis after surgical operation, artificial stool / joint replacement Thrombosis, thromboembolism after total hip arthroplasty (THR), thromboembolism after total knee arthroplasty (TKR), thromboembolism after hip fracture surgery (HFS), thrombosis after thromboplasty and / or reclosure, burger disease, explosive vascular Preventive and / or therapeutic agents for internal coagulation syndrome, systemic inflammatory response syndrome (SIRS), multi-organ failure (MODS), blood clot formation during extracorporeal circulation or blood coagulation during blood collection Standing useful.

The present invention is a compound represented by Formula 1, or a pharmaceutically acceptable salt or hydrate thereof; And a pharmaceutical composition comprising a preparation comprising pea starch as a coating agent in a therapeutically effective amount.

 The present invention provides the use of an agent according to the invention for the manufacture of a medicament for the prophylaxis or treatment of thrombotic disease.

The statements mentioned in the formulations of the present invention may equally apply to pharmaceutical compositions, methods of treatment and uses, unless they contradict each other.

The formulation comprising the edoxaban of the present invention as an active ingredient shows an excellent dissolution pattern and excellent bioavailability and significantly reduces the time and cost in the preparation of the formulation through the low viscosity of the coating agent, the characteristics of the formulation itself and its manufacturing method Excellent effect in terms of appearance.

Hereinafter, examples will be described in detail to help understand the present invention. However, the following examples are merely to illustrate the content of the present invention is not limited to the scope of the present invention. The embodiments of the present invention are provided to more completely explain the present invention to those skilled in the art.

Example 1 Preparation of Tablets Containing Edoxaban Citrate Monohydrate

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 were mixed with HSM (100 mL of purified water). High speed mixer). HSM (SM-5C, Sejong Pharmatech) was used for wet granulation. The granules were dried in a fluid bed dryer. Fluid bed dryer was used (GPCG-1, Glatt GmbH). The dried granules were sized with a sizing machine. The sizing machine used Comil (197, Quadro). 16.00 g of crospovidone are mixed with 352.80 g of the formulation and mixed with 28.00 g of talc and 3.20 g of colloidal silicon oxide. The final mixture was compressed 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 iron oxide were added to a homogenizer (Ultra-turrax T). 50, IKA) to prepare a suspension and then stir. Tablets were placed in a coating machine (LCM, O'HARA) and film-coated so that the coating amount was 12 mg / tablet with a suspension of 15 w / w%.

Its specific composition is shown in Table 1 below.

Table 1 Composition of Edoxaban Citrate Monohydrate

Examples 2 to 11. Preparation of tablets containing Edoxaban

Tablets were prepared for the Edoxaban of 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 purified by HSM (High Speed Mixer) using purified water. In each of the above Edoxaban granulation process, purified water was used in excess of 10% of the total weight. HSM (SM-5C, Sejong Pharmatech) was used for wet granulation. The granules were dried in a fluid bed dryer. Fluid bed dryer was used (GPCG-1, Glatt GmbH). The dried granules were sized with a sizing machine. The sizing machine used Comil (197, Quadro). Add the remaining crospovidone to the formulation and mix, add talc and colloidal silicon oxide. The final mixture was compressed using a single tablet press (EK-O, Korsch) and rotary tablet press (GRC-7S, Sejong Pharmatech). Prepurified hydroxypropyl pea starch, D-sorbitol, propylene glycol 6000, titanium oxide and yellow iron oxide were added to purified water, and a suspension was prepared by using a homogenizer (Ultra-turrax T 50, IKA) and stirred. The tablets were put into a coating machine (LCM, O'HARA) and the film was coated with a coating suspension so that the coating amount was 12 mg / tablet.

Examples 12 to 22. Preparation of tablets containing Edoxaban

As shown in Table 1 and Table 3, D-mannitol, pregelatinized starch, crospovidone, hydroxypropyl cellulose and edoxaban, or a pharmaceutically acceptable salt or hydrate thereof are mixed, and then talc and colloidal silicon oxide are added thereto. Mixed. The final mixture was compressed using a single tablet press (EK-0, Korsch) and a rotary tablet press (GRC-7S, Sejong Pharmatech). Prepurified hydroxypropyl pea starch, D-sorbitol, propylene glycol 6000, titanium oxide and yellow iron oxide were added to purified water, and a suspension was prepared by using a homogenizer (Ultra-turrax T 50, IKA) and stirred. Tablets were placed in a coating machine (LCM, O'HARA) and film-coated so that the coating amount was 12 mg / tablet as a coating suspension.

Comparative Examples 1 and 2. Preparation of Tablets Containing Edoxaban Tosylate Monohydrate

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

Table 4 Edoxaban 30 mg tablets (Comparative Example 1)

Table 5 Edoxaban 60 mg tablets (Comparative Example 2)

Experimental Example 1. Confirm the coating time shortened

The time taken from the uncoated tablet to the completion of the coating in the preparation process of the formulation of Example 1 and Comparative Example 2 was compared.

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

On the other hand, in the case of preparing the coated tablet of the formulation of Comparative Example 2 it took about 72 minutes to confirm that more than about 40 minutes. Moreover, the coated tablets of Comparative Example 2 required further drying time after coating, confirming that the tablet preparation required a very long time. In addition, in the manufacture of the coated tablet of Comparative Example 2, the bearding phenomenon occurred after the coating of the tablet due to the high viscosity of the coating agent. Accordingly, a problem arises in that the coating cannot be performed immediately and the cleaning operation of the device is performed, which significantly delays the preparation process of the preparation.

That is, as described above, in contrast to the method of the comparative example, the present invention not only significantly shortens the coating time by changing the coating agent, but also does not require an additional drying or device cleaning step required after preparing the coated tablet. It has excellent advantages in the manufacturing process. This has been shown to significantly increase the cost and time efficiency in the preparation of the formulation.

Experimental Example 2. Check dissolution rate

As a dissolution test solution, the KP 11 dissolution test method 2 (paddle) using pH 1.2 solution (the first solution of KP 11 disintegration test method), pH 4.0 solution, the pH 6.8 solution (the second solution of KP 11 disintegration test method), and water Elution test at 50 rpm.

For dissolution rate testing, 60 mg of Lyxiana tablets were used as the formulation of Example 1 and commercially available Edoxaban tablets.

For pH 1.2 solution (1st solution of KP 11 disintegration test method), pH 4.0 solution and water, samples of dissolution test solutions were taken at 5, 10 and 15 minutes after the start of the test, and only 5, 10, 15, 30 in pH 6.8 solution. Samples of dissolution test solutions were taken at 60, and 120 minutes. The liquid chromatography was analyzed under the following conditions, and the results are shown in Tables 6 to 9.

<Liquid chromatography conditions>

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

Column temperature: 25 ° C.

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 absorption photometer (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 confirmed in the above table, it was confirmed that the formulation of Example 1 exhibited a similar dissolution phenomenon as compared to a commercially available product.

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

From the above description, those skilled in the art will appreciate that the present invention can be implemented in other specific forms without changing the technical spirit or essential features. In this regard, it should be understood that the embodiments described above are exemplary in all respects and are not intended to limit the invention. The scope of the present invention should be construed that all changes or modifications derived from the meaning and scope of the following claims and equivalent concepts rather than the detailed description are included in the scope of the present invention.

Claims (17)

1. A compound represented by Formula 1, or a pharmaceutically acceptable salt or hydrate thereof; And pea starch as coating agent.

   [Formula 1]

   

   .
2.  The formulation of claim 1, wherein the formulation is a tablet.
3. According to claim 1, wherein the pharmaceutically acceptable salt of the compound represented by Formula 1 is a group consisting of tartarate, hydrochloride, citrate, malate, phosphate, sulfate, malonate, oxalate, bromate and tosylate The formulation is any one selected from.
4. The preparation according to claim 1, wherein the hydrate of the compound represented by Formula 1 is a monohydrate of citrate of the compound represented by Formula 1.
5. The formulation of claim 1, wherein the pea starch is pregelatinized hydroxypropyl pea starch.
6. According to claim 1, wherein the compound represented by the formula (1), or a pharmaceutically acceptable salt or hydrate thereof 7 to 30% by weight relative to the total weight of the formulation; And

   Formulations comprising 1 to 7% by weight of the coating agent based on the total weight of the formulation.
7. The formulation of claim 1, wherein the formulation comprises at least one excipient selected from the group consisting of mannitol, erythritol, xylitol, pregelatinized starch and crystalline cellulose;

   At least one binder selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methyl cellulose, povidone and vinylpyrrolidone;

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

   And at least one disintegrant selected from the group consisting of crospovidone, carmellose and carboxy methyl starch sodium.
8. A method for preparing a formulation comprising coating a compound represented by Formula 1, or a pharmaceutically acceptable salt or hydrate thereof, with pea starch.

    [Formula 1]

   

   .
9. The method of claim 8, wherein the formulation is a tablet and the preparation of the formulation is by wet granulation, dry granulation or direct tableting.
10. The method of claim 8, wherein the method of preparing the formulation

    (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 with the mixture; And

    (c) coating the uncoated tablets with pea starch.
11. The method of claim 10,

    Wherein (a) step is to include more than 10% moisture when mixed, the preparation method of the preparation.
12. The method of claim 10,

    In the step (c) further comprises a sorbitol and propylene glycol as a coating agent, the preparation method of the preparation.
13. A pharmaceutical composition comprising a formulation according to any one of the preceding claims.
14. A method for preventing or treating thrombotic disease, comprising administering a therapeutically effective amount of the agent according to any one of claims 1 to 7.
15. The method of claim 14, wherein the thrombotic disease is at least one selected from the group consisting of cerebral infarction, cerebral embolism, pulmonary infarction, pulmonary embolism, myocardial infarction, angina pectoris, thrombosis and embolism.
16. A formulation according to any one of claims 1 to 7 for use in the prevention or treatment of thrombotic disease.
17. Use of a formulation according to any one of claims 1 to 7 for the manufacture of a medicament for the prevention or treatment of thrombotic disease.