JP2022507838A - Pharmaceutical preparations containing edoxaban and methods for manufacturing them - Google Patents

Abstract

The present invention relates to a preparation containing edoxaban as an active ingredient and a method for producing the same. The pharmaceutical product containing edoxaban as an active ingredient of the present invention exhibits an excellent elution pattern, has excellent bioavailability, and the low viscosity of the coating agent significantly reduces the time and cost in manufacturing the pharmaceutical product, thereby significantly reducing the time and cost in manufacturing the pharmaceutical product itself. It shows excellent effects in terms of the manufacturing method.

Description

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

Edoxaban is a compound that inhibits activated blood coagulation factor X (also referred to as activated factor X or FXa) and is useful as a prophylactic and / or therapeutic agent for thrombotic diseases, and is represented by the following chemical formula 1. 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.

Edoxaban is commercialized in the form of p-toluenesulfonate monohydrate represented by the following chemical formula 2 and sold as Lixiana.

It is well known that the compound of Chemical Formula 1 exhibits good solubility in a strongly acidic aqueous solution, but its solubility decreases in an aqueous solution in a neutral region (for example, a neutral buffer solution). Therefore, although much research and development on edoxaban formulation has been carried out to solve such a problem, sufficient effect could not be achieved.

In addition, various methods currently known have great disadvantages in manufacturing efficiency and manufacturing unit price because they take a considerable amount of time in the manufacturing process.

Against this background, the present inventors have developed a novel formulation containing edoxaban as an active ingredient and a method for producing the same, and have completed the present invention.

Republic of Korea Published Patent No. 10-2018-0022125

The present invention provides a compound represented by the following chemical formula 1, or a pharmaceutically acceptable salt or hydrate thereof; and a preparation containing pea starch as a coating agent.

The present invention provides a method for producing a pharmaceutical product, which comprises the step of coating the compound represented by the chemical 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 provides a compound represented by the following chemical formula 1, or a pharmaceutically acceptable salt or hydrate thereof; and a preparation containing pea starch as a coating agent.

The compound represented by the chemical formula ¹ is N1- (5-chloropyridin- ² -yl) -N2-((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-[(. It is named 5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] aminocyclohexyl) ethandiamide and is called edoxaban.

In the present invention, a pharmaceutically acceptable salt is a physiologically acceptable salt that, when administered to a human, usually does not cause an allergic reaction such as gastrointestinal disorder, dizziness or a similar reaction, and is the art of the art. It means the one normally used in the manufacture of pharmaceutical preparations by a person who has the usual knowledge in.

Such a pharmaceutically acceptable salt means a salt formed with an inorganic acid or an organic acid or a base.

Specifically, any one selected from the group consisting of tartrate, hydrochloride, citrate, malate, phosphate, sulfate, malonate, oxalate, bromine and tosylate. There may be one.

In the present invention, the "hydrate" is a combination of water with edoxaban or a pharmaceutically acceptable salt thereof by a non-covalent intermolecular force, and is a stoichiometric amount of water. May be included. Specifically, the hydrate contains about 0.25 mol to about 10 mol of water based on 1 mol of the active ingredient, and more specifically, about 0.5 mol, about 1 mol, about. It can contain 1.5 mol, about 2 mol, about 2.5 mol, about 3 mol, about 5 mol and the like. Preferably, the hydrate may be a monohydrate of edoxabankenate.

In the present invention, the pea starch means starch derived from pea. This is starch with an amylose content of at least about 50% by weight of starch. The pea starch was not only a non-modified pea starch, but also a modified functional group (eg, a hydroxyl group) of the starch (eg, substituted with a C2-C8 hydroxyalkyl group, such as a hydroxypropyl or hydroxyethyl group). Also contains pea starch. Preferred examples of such modified pea starch include pregelatinized hydroxypropyl pea starch. Pregelatinized hydroxypropyl pea starch contains, for example, a hydroxypropyl group at 2-7%. Examples of such modified pea starch include lycoat (Lycoat®). Specifically, Lycoa (registered trademark) RS780, Lycoat (Lycoat (registered trademark))
Registered trademark)) Includes RS720 and the like.

In the present invention, the pharmaceutical product uses pea starch as a coating agent. By using pea starch as a coating agent, such a pharmaceutical product of the present invention exhibits an excellent elution pattern and is excellent in bioavailability. In particular, it has the advantage of showing a similar elution pattern when compared to commercially available drugs, and its low viscosity significantly reduces the time and cost in manufacturing the pharmaceutical product.

The pharmaceutical product of the present invention is preferably a tablet.
The tablet according to the present invention can be produced by a wet granulation, direct tableting or dry granulation method, and preferably can be produced by wet granulation or direct tableting.

In the above-mentioned preparation, the compound represented by Chemical Formula 1 is contained in an amount of 7 to 30% by weight, preferably 10 to 25% by weight, based on the total weight of the preparation.

In the above-mentioned preparation, the coating agent containing pea starch is contained in an amount of 1 to 7% by weight, preferably 1.5 to 5% by weight, based on the total weight of the preparation.

The pharmaceutical product of the present invention can 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 improve the solubility of compounds of formula 1 and help elution. In the above-mentioned preparation, the excipient is contained in an amount of 40 to 80% by weight, preferably 50 to 70% by weight, based on the total weight of the preparation.

The pharmaceutical product of the present invention can contain any one or more disintegrants selected from the group consisting of crospovidone, carmellose and sodium carboxymethyl starch as disintegrants. Preferably, the disintegrant is crospovidone. In the above-mentioned preparation, 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 preparation.

The pharmaceutical product of the present invention can contain any one or more binders selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methyl cellulose, povidone and vinylpyrrolidone as the binder. Preferably, the binder is hydroxypropyl cellulose. In the above-mentioned preparation, the binder is contained in an amount of 3 to 15% by weight, preferably 4 to 10% by weight, based on the total weight of the preparation.

The pharmaceutical product of the present invention can contain any one or more lubricants selected from the group consisting of talc, colloidal silicon dioxide, magnesium stearate and sodium stealylate fumarate as lubricants. Preferably, the lubricant is talc and colloidal silicon dioxide. In the above-mentioned preparation, the lubricant is contained in an amount of 3 to 15% by weight, preferably 4 to 10% by weight, based on the total weight of the preparation.

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

Further, the present invention can further contain a colorant, and can further contain, for example, a commonly used colorant such as titanium oxide and yellow iron oxide.

The pharmaceutical product of the present invention is preferably a compound represented by Chemical Formula 1, or a pharmaceutically acceptable salt or hydrate thereof;
One or more excipients selected from the group consisting of mannitol, erythritol, xylitol, pregelatinized starch and crystalline cellulose;
One or more binders selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methyl cellulose, povidone and vinylpyrrolidone;
One or more lubricants selected from the group consisting of talc, colloidal silicon dioxide, magnesium stearate and sodium stearyl fumarate;
One or more disintegrants selected from the group consisting of crospovidone, carmellose and sodium carboxymethyl starch; and a coating of pea starch.

More preferably, the pharmaceutical product of the present invention is a compound represented by Chemical Formula 1, or a pharmaceutically acceptable salt or hydrate thereof;
Excipients of mannitol and pregelatinized starch;
Hydroxypropyl cellulose binder;
Talc and colloidal silicon dioxide lubricants;
Provided are a formulation containing a disintegrant of crospovidone; and a coating agent of pea starch.

The preparation according to the present invention is a preparation for use in the prevention or treatment of thrombotic diseases. For example, the thrombotic disease may be one or more selected from the group consisting of cerebral infarction, cerebral embolism, pulmonary infarction, pulmonary embolism, myocardial infarction, angina, thrombosis and embolism.

The present invention provides a method for producing a pharmaceutical product, which comprises the step of coating the compound represented by the chemical formula 1 or a pharmaceutically acceptable salt or hydrate thereof with pea starch.

The pharmaceutical product according to the present invention is preferably a tablet and can be produced by wet granulation, dry granulation or direct tableting. More preferably, it can be produced by a wet granulation method or a direct tableting method.

The method for producing the above-mentioned preparation is preferably
(A) The step of mixing the compound represented by the chemical formula 1 or a pharmaceutically acceptable salt thereof with an excipient, a binder, a disintegrant and a lubricant;
(B) The step of making an uncoated tablet using the mixture; and (c) the step of coating the uncoated tablet with pea starch.

In the above-mentioned production method, the excipient, the binder, the disintegrant and the lubricant are as described in the above-mentioned preparation.

The steps (a) and (b) can be appropriately modified by wet granulation or direct tableting to a level normally applicable.

In the step (a), the water content is preferably contained in excess of 10%. By containing more than 10% of water, the flowability of the mixture can be improved by producing large granules in the mixing step.

In addition to pea starch, the coating in step (c) can further contain sorbitol and propylene glycol as components of the coating agent.

By using the pea starch, the low viscosity of the coating agent can be provided and the coating can be performed quickly and quickly.

The method for producing a pharmaceutical product according to the present invention exhibits an excellent effect in terms of the pharmaceutical product and the manufacturing method thereof by providing a pharmaceutical product having an excellent dissolution rate and significantly reducing the time and cost in manufacturing the pharmaceutical product. ..

The present invention provides a pharmaceutical composition comprising the compound represented by the above chemical formula 1, or a pharmaceutically acceptable salt or hydrate thereof; and a preparation containing pea starch as a coating agent.

Since the pharmaceutical composition exhibits a highly activated blood coagulation factor X (FXa) inhibitory action, it is useful as a blood coagulation preparation, a prophylactic and / or therapeutic agent for thrombus or embolism. The pharmaceutical composition of the present invention is a medicine for mammals including humans, an activated blood coagulation factor X inhibitor, a blood coagulation inhibitor, a thrombosis and / or a prophylactic and / or therapeutic agent for thrombosis, a thrombotic disease. Prophylactic and / or therapeutic agents, as well as thrombosis and / or thrombosis associated with cerebral infarction, cerebral embolism, pulmonary infarction, pulmonary embolism, myocardial infarction, angina, non-valvular atrial fibrillation (NVAF), deep venous thrombosis Disease, deep venous thrombosis after surgical operation, thrombosis after artificial valve / joint replacement, thrombosis after total hip replacement (THR), thrombosis after total knee replacement (TKR), hip joint Thrombosis after fracture surgery (HFS), thrombosis and / or reocclusion after blood circulation reconstruction, Buerger's disease, generalized intravascular coagulation syndrome, systemic inflammatory reaction syndrome (SIRS), multi-organ failure (MODS) It is useful as a prophylactic and / or therapeutic agent for thrombosis during extracorporeal circulation or blood coagulation during blood collection.

The present invention therapeutically comprises a pharmaceutical composition comprising the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt or hydrate thereof; and a preparation containing pea starch as a coating agent. Provided is a method for preventing or treating a thrombotic disease, which is administered in an effective amount.

The present invention provides the use of the pharmaceutical product according to the present invention for producing a drug for preventing or treating a thrombotic disease.

The matters mentioned in the formulations of the present invention are similarly applicable to pharmaceutical compositions, therapeutic methods and uses, as long as they do not conflict with each other.

The pharmaceutical product containing edoxaban as an active ingredient of the present invention exhibits an excellent elution pattern, has excellent bioavailability, and the low viscosity of the coating agent significantly reduces the time and cost in manufacturing the pharmaceutical product, thereby reducing the characteristics of the pharmaceutical product itself. It shows excellent effects in terms of and its manufacturing method.

Hereinafter, examples will be described in detail to help the understanding of the present invention. However, the following examples are merely for exemplifying the contents of the present invention, and the scope of the present invention is not limited to the following examples. The embodiments of the invention are provided to more fully explain the invention to those with average knowledge in the art.

Example 1. Preparation of Tablets Containing Edoxabank Enate Monohydrate 153.79 g D-mannitol, 84.00 g pregelatinized starch, 4.00 g crospovidone, 28.00 g hydroxypropyl cellulose and 83.01 g After mixing the edoxabanate monohydrate, granulation was performed by HSM (High Speed Mixer) using 100 mL of purified water. HSM (SM-5C, SEJONG PHARMATECH) was used for wet granulation. The granulated product was dried using a fluidized bed dryer. As a fluidized bed dryer, a Fluid bed dryer (GPCG-1, Glatt GmbH) was used. The dried granules were sized using a sizing machine. As a sizing machine, Comil (197, Quadro) was used. After adding 16.00 g of crospovidone to 352.80 g of sizing material and mixing, 28.00 g of talc and 3.20 g of colloidal silicon dioxide are added and mixed. The final mixture was locked using a single-shot locker (EK-0, Korch) and a rotary locker (GRC-7S, SEJONG PHARMATECH).

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 in 67.80 mL of purified water. Add and stir after making a suspension using a homogenizer (Ultra-turrax T 50, IKA). The tablets were placed in a coating machine (LCM, O'HARA) and film-coated with a 15 w / w% suspension so that the coating amount was 12 mg / tablet.
The specific composition is shown in Table 1 below.

Examples 2 to 11. Preparation of Tablets Containing Edoxaban Tablets were prepared for edoxaban in Table 2 below, or a pharmaceutically acceptable salt or hydrate thereof.

As shown in Table 3, D-mannitol; pregelatinized starch; some crospovidone; hydroxypropyl cellulose; and edoxaban, or a pharmaceutically acceptable salt or hydrate thereof, are mixed and then purified water is used. And granulated by HSM (High Speed Mixer). Purified water was used in excess of 10% of the total weight in each of the above edoxaban granulation processes. HSM (SM-5C, SEJONG PHARMATECH) was used for wet granulation. The granulated product was dried using a fluidized bed dryer. As a fluidized bed dryer, a Fluid bed dryer (GPCG-1, Glatt GmbH) was used. The dried granules were sized using a sizing machine. As a sizing machine, Comil (197, Qua)
dr) was used. Add the remaining crospovidone to the sizing and mix, then add talc and colloidal silicon dioxide and mix. The final mixture was locked using a single-shot locker (EK-O, Korch) and a rotary locker (GRC-7S, SEJONG PHARMATECH). Pregelatinized hydroxypropyl pea starch, D-sorbitol, propylene glycol 6000, titanium oxide and yellow iron oxide are added to purified water, and a suspension is prepared using a homogenizer (Ultra-turrax T50, IKA) and then stirred. .. The tablets were placed in a coating machine (LCM, O'HARA) and film-coated with a coating suspension so that the coating amount was 12 mg / tablet.

Examples 12-22. Preparation of Tablets Containing Edoxaban As shown in Tables 1 and 3, after mixing D-mannitol, pregelatinized starch, crospovidone, hydroxypropyl cellulose and edoxaban, or a pharmaceutically acceptable salt or hydrate thereof. , Starch and colloidal silicon dioxide were added and further mixed. The final mixture was locked using a single-shot locker (EK-0, Korch) and a rotary locker (GRC-7S, SEJONG PHARMATECH). Add pregelatinized hydroxypropyl pea starch, D-sorbitol, propylene glycol 6000, titanium oxide and yellow iron oxide to purified water and homogenizer (Ultra-turrax T).
A suspension was prepared using 50, IKA) and then stirred. The tablets were placed in a coating machine (LCM, O'HARA) and film-coated with a coating suspension so that the coating amount was 12 mg / tablet.

Comparative Examples 1 and 2. Production of Tablets Containing Edoxavantosilate Monohydrate Based on the dosage form examples described in Examples of Korean Registered Patent No. 10-1424843, tablets were produced with the compositions shown in Tables 4 and 5 below. ..

Experimental example 1. Confirmation of shortening of coating time In the manufacturing process of the above-mentioned pharmaceutical product of Example 1 and the pharmaceutical product of Comparative Example 2, the time required from the uncoated tablet to the completion of coating was compared.

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

On the other hand, in the case of producing the coated lock of the pharmaceutical product of Comparative Example 2, it was confirmed that it took about 72 minutes and further took about 40 minutes or more. Furthermore, in the case of the coated tablet of Comparative Example 2, it was confirmed that an additional drying time was required after coating, and a considerably long time was required to produce the tablet. Further, in the production of the coated tablet of Comparative Example 2, the bearding phenomenon occurred after the tablet coating due to the high viscosity of the coating agent. As a result, the coating could not be performed immediately again, and the equipment had to be cleaned, which caused a problem that the manufacturing process of the pharmaceutical product was considerably delayed.

That is, as described above, when compared to the methods of Comparative Examples, the present invention not only significantly reduces the coating time through changes in the coating agent, but also requires additional drying or equipment after the manufacture of the coated tablets. It has an excellent advantage in the manufacturing process in that it does not require a cleaning step. It was confirmed that this would greatly improve the cost and time efficiency in the manufacture of the pharmaceutical product.

Experimental example 2. Confirmation of elution rate KP11 elution test using pH 1.2 solution (first solution of KP11 disintegration test method), pH 4.0 solution, pH 6.8 solution (second solution of KP11 disintegration test method) and water as elution test solutions. The second method (paddle method), the dissolution test was performed at 50 rpm.

In the dissolution rate test, 60 mg of Lixiana tablets was used as the edoxaban tablet on the market and the preparation of Example 1.

For pH 1.2 solution (first solution of KP11 disintegration test method), pH 4.0 solution and water, elution test solution samples were taken at 5, 10 and 15 minutes from the start of the test, and only in pH 6.8 solution. Dissolution test solution samples were taken at 5, 10, 15, 30, 60 and 120 minutes. The analysis was performed by the liquid chromatography method under the following conditions, and the results are shown in Tables 6-9.

<Conditions for liquid chromatography>
-Column: A column in which a stainless steel tube having an inner diameter of 4.6 mm and a length of 250 mm is filled with octadecylsilyl silica gel for liquid chromatography of 5 μm or an equivalent column (XTerra C18, 4.6 × 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 velocity: 1.0 mL / min * Detector: ultraviolet absorptiometer (measurement wavelength 290 nm)

As can be confirmed above, it was confirmed that the pharmaceutical product of Example 1 showed a substantially similar elution phenomenon when compared with the product on the market.

That is, the present invention provides an excellent pharmaceutical product by exhibiting an elution rate equivalent to that of a commercially available pharmaceutical product, significantly shortening the production time, and significantly reducing the cost required for the production process.

From the above explanation, it is understood that an ordinary engineer in the technical field to which the present invention belongs can implement the present invention in another concrete form without changing its technical idea or essential features. Will be able to. In this context, it should be understood that the examples described above are exemplary in all respects and are not intended to limit the invention. The scope of the present invention shall be construed as including the meaning and scope of the claims described below and all modified or modified forms derived from the equivalent concept thereof from the above detailed description. Must be.

Claims (17)

A compound represented by the following chemical formula 1, or a pharmaceutically acceptable salt or hydrate thereof; and a preparation containing pea starch as a coating agent.

The preparation according to claim 1, wherein the preparation is a tablet. The pharmaceutically acceptable salts of the compound represented by the chemical formula 1 are tartrate, hydrochloride, citrate, malate, phosphate, sulfate, malonate, oxalate and bromine acid. The preparation according to claim 1, which is any one selected from the group consisting of a salt and a tosylate. The preparation according to claim 1, wherein the hydrate of the compound represented by the chemical formula 1 is a monohydrate of the citrate of the compound represented by the chemical formula 1. The preparation according to claim 1, wherein the pea starch is pregelatinized hydroxypropyl pea starch. The compound represented by the chemical formula 1 or a pharmaceutically acceptable salt or hydrate thereof is added in an amount of 7 to 30% by weight based on the total weight of the preparation; The preparation according to claim 1, which comprises 7% by weight. The formulation is one or more excipients selected from the group consisting of mannitol, erythritol, xylitol, pregelatinized starch and crystalline cellulose;
One or more binders selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methyl cellulose, povidone and vinylpyrrolidone;
One or more lubricants selected from the group consisting of talc, colloidal silicon dioxide, magnesium stearate and sodium stearyl fumarate; and any selected from the group consisting of crospovidone, carmellose and sodium carboxymethyl starch. The preparation according to claim 1, further comprising one or more disintegrants. A method for producing a preparation comprising a step of coating a compound represented by the following Chemical Formula 1 or a pharmaceutically acceptable salt or hydrate thereof with pea starch.

The method for producing a pharmaceutical product according to claim 8, wherein the pharmaceutical product is a tablet, and the pharmaceutical product is produced by wet granulation, dry granulation, or direct tableting. The manufacturing method of the formulation is
(A) The step of mixing the compound represented by the chemical formula 1 or a pharmaceutically acceptable salt thereof with an excipient, a binder, a disintegrant and a lubricant;
The method for producing a pharmaceutical product according to claim 8, comprising (b) a step of producing an uncoated tablet using the mixture; and (c) a step of coating the uncoated tablet with pea starch. The method for producing a pharmaceutical product according to claim 10, wherein the step (a) contains more than 10% of water when mixed. The method for producing a pharmaceutical product according to claim 10, further comprising sorbitol and propylene glycol as a coating agent in the step (c). A pharmaceutical composition comprising the pharmaceutical product according to any one of claims 1 to 7. A method for preventing or treating a thrombotic disease, which comprises administering the preparation according to any one of claims 1 to 7 in a therapeutically effective amount. The method according to claim 14, wherein the thrombotic disease is one or more selected from the group consisting of cerebral infarction, cerebral embolism, pulmonary infarction, pulmonary embolism, myocardial infarction, angina, thrombosis and embolism. .. The preparation according to any one of claims 1 to 7, for use in the prevention or treatment of a thrombotic disease. Use of the preparation according to any one of claims 1 to 7 for producing a drug for preventing or treating a thrombotic disease.