KR20190040764A - Pharmaceutical formulation comprising Ticagrelor and preparation method thereof - Google Patents

Abstract

The present invention relates to a pharmaceutical composition containing ticagrelor and a method for manufacturing the same. More specifically, the present invention relates to: the pharmaceutical composition which contains ticagrelor and at least one pharmaceutical excipient as active components and exhibits elution profile, wherein at least 90% of the total weight of the active components are eluted at the time of 30 to 90 minutes from the start of a dissolution test in a buffer solution of pH 4.0 to 7.0; and the method for manufacturing the same. The pharmaceutical composition containing ticagrelor of the present invention as the active component is a formulation, in which the solubility of ticagrelor known as a poorly soluble drug is improved, especially since 90% or more of active components are released within 30 to 90 minutes and desired pharmacokinetic results can be obtained, it is possible to develop the formulation which can increase drug compliance of patients.

Description

Pharmaceutical compositions comprising Ticagrella and methods for preparing the same are disclosed.

The present invention relates to a pharmaceutical composition comprising tikageler, and more particularly to a pharmaceutical composition comprising a tikagreler as an active ingredient and at least one pharmaceutical excipient, Wherein at least 90% of the total weight of the active ingredient is eluted at the time of 30 minutes to 90 minutes from the start of the test in the dissolution test.

(1S, 2S, 3R, 5S) -3- [7 - [[(1R, 2S) -2- (3,4- di (4-fluorophenyl) cyclopropyl] amino] -5- (propylthio) -3H-1,2,3-triazolo [4,5- d] pyrimidin- Propoxy) cyclopentane-1,2-diol, which is used as an antithrombotic agent.

[Chemical Formula]

According to the US Food and Drug Administration's Biopharmaceutical Classification System (BCS), ticagrella is an insoluble drug in Class IV (low permeability, low solubility).

According to the Korean Food and Drug Administration Notification No. 200-26 (enacted on June 27, 2000) regarding the drug equivalence test standard, a solubilizing agent is to be used in the elution test of a poorly soluble preparation. Thus, commercially available Brilinta Tab. (90 mg) was evaluated by eluting with 1% polysorbate 80%, and the dissolution rate was not more than 90% in eluates having different pH (pH 6.8, 4.0 and water) .

Korean Patent No. 10-1539467 discloses a pharmaceutical composition containing ticagrella as a prior art. However, since the dissolution rate is not more than 90%, the oral administration of ticagrella as an active ingredient It is urgent to improve the solubilization of drag formulation.

As a result of intensive efforts to develop a pharmaceutical composition capable of improving solubility without using a solubilizing agent, the present inventors have found a composition capable of remarkably improving the dissolution rate by changing the type of excipient, the mixing ratio, and the manufacturing process of the formulation And completed the present invention.

It is an object of the present invention to provide a pharmaceutical composition containing tikagreler or a salt thereof and at least one pharmaceutical excipient as an active ingredient and having a pH of 4.0 to pH 7.0 at 30 to 90 minutes from the start of the dissolution test in the buffer solution, Wherein at least 90% of the weight of the composition is eluted.

Another object of the present invention is to provide a pharmaceutical composition comprising 20 to 45% by weight of ticagrella as active ingredient, 20 to 45% by weight of D-mannitol, 10 to 30% by weight of microcrystalline cellulose, 2 to 6% by weight of croscarmellose sodium, And 0.5 to 3% by weight of cellulose.

It is still another object of the present invention to provide a method for preparing a mixture of a tikageler, an excipient and a disintegrant as an active ingredient, mixing and sieving the mixture, mixing the binder with the binder, granulating, Mixing the sizing product with a lubricant, and molding the granulated product through the lubricating process.

Disclosure of the Invention The present invention has been made in order to solve the above-mentioned problems, and has as its object to provide a pharmaceutical composition containing tikagreler or a salt thereof and at least one pharmaceutical excipient as an active ingredient in a buffer solution of pH 4.0 to pH 7.0, Wherein at least 90% of the total weight of the active ingredient is eluted at the time of the elution.

The pharmaceutical composition of the present invention is suitable for oral administration. Bioavailability is important in pharmaceutical compositions suitable for oral administration. Bioavailability is the relative amount at which the drug reaches the systemic circulation in a form that is unaltered relative to the dose administered, and is important in determining the therapeutically active concentration at the site of action. Since both the drug release from the formulation and the stability of the formulation affect bioavailability, it is important that the drug formulation substantially releases all active drug.

In the present invention, the dissolution test may be performed at 37 占 0.5 占 폚, 1% polysorbate 80 solution, 50 rpm according to Korean Pharmacopoeia dissolution assay method No. 2 (paddle method).

The pharmaceutical composition of the present invention can be used for the dissolution test

(a) 90% or more of the total weight of tikageler is eluted at 45 minutes after the start of the test when the pH of the buffer solution is 4.0;

(b) 90% or more of the total weight of tikageler is eluted 90 minutes after the start of the test when the pH of the buffer solution is 6.8; Also

(c) A pH of the buffer solution of 7.0 may exhibit a dissolution profile in which at least 90% of the total weight of tikagelerel is eluted at 30 minutes after the initiation of the test.

In one embodiment of the present invention, the acetic acid buffer solution was used as the buffer solution having pH 4.0 in the polysorbate solution during the dissolution test, and the phosphate buffer solution was used as the buffer solution having the pH of 6.8. Purified water was mixed for pH 7.0 conditions.

In the present invention, the pharmaceutical excipient may be at least one selected from the group consisting of D-mannitol, microcrystalline cellulose, croscarmellose sodium, hydroxypropylcellulose, and glidant, but is not limited thereto.

In the present invention, the mixture of D-mannitol and microcrystalline cellulose may be contained in an amount of 30 to 70% by weight based on the total weight of the composition.

In the present invention, the D-mannitol may be contained in an amount of 20 to 45 wt% of the total weight of the composition.

In the present invention, the microcrystalline cellulose may include 10 to 30% by weight of the total weight of the composition.

In the present invention, the croscarmellose sodium may be contained in an amount of 1 to 6% by weight based on the total weight of the composition.

In the present invention, the hydroxypropyl cellulose may be contained in an amount of 0.5 to 3% by weight based on the total weight of the composition.

In the present invention, the lubricant may be one selected from the group consisting of magnesium stearate, sodium stearyl fumarate, talc, stearic acid, palmitic acid, calcium stearate, carnauba wax, hydrogenated vegetable oil, mineral oil, polyethylene glycol, May be selected, and magnesium stearate is preferably selected, but not limited thereto.

In the present invention, the lubricant may be contained in an amount of 0.5 to 3% by weight based on the total weight of the composition.

The pharmaceutical composition of the present invention may further contain preservatives, stabilizers, antioxidants, silica flow conditioning agents, anti-adhesion agents or fluidizers as conventional excipients.

The present invention also provides a pharmaceutical composition comprising 20 to 45% by weight of tikagelere as active ingredient, 20 to 45% by weight of D-mannitol, 10 to 30% by weight of microcrystalline cellulose, 2 to 6% by weight of croscarmellose sodium, 3% < / RTI > by weight of the composition.

The pharmaceutical composition of the present invention may further comprise 0.5 to 3% by weight of a lubricant. The lubricant may be at least one selected from the group consisting of magnesium stearate, sodium stearyl fumarate, talc, stearic acid, palmitic acid, calcium stearate, carnauba wax, hydrogenated vegetable oil, mineral oil, polyethylene glycol and silicon dioxide And magnesium stearate is preferably selected, but not limited thereto.

In the present invention, the pharmaceutical composition may exhibit a dissolution profile in which at least 90% of the total weight of the active ingredient is eluted at 30 to 90 minutes after the initiation of the dissolution test in a buffer solution of pH 4.0 to pH 7.0.

In the present invention, the dissolution test may be carried out at 37 ± 0.5 ° C., 1% polysorbate 80 solution, 50 rpm according to Korean Pharmacopoeia dissolution assay method No. 2 (paddle method).

The pharmaceutical composition of the present invention can be used for the dissolution test

(a) 90% or more of the total weight of tikageler is eluted at 45 minutes after the start of the test when the pH of the buffer solution is 4.0;

(b) 90% or more of the total weight of tikageler is eluted 90 minutes after the start of the test when the pH of the buffer solution is 6.8; Also

(c) A pH of the buffer solution of 7.0 may exhibit a dissolution profile in which at least 90% of the total weight of tikagelerel is eluted at 30 minutes after the initiation of the test.

Mixing and sieving the tikageler, the excipient and the disintegrant as the active ingredient of the present invention, mixing the binder with the binder, granulating the granules, drying and granulating the granules, Mixing the lubricant with the lubricant, and shaping the granulated product through the lubricating process.

In the present invention, the pharmaceutical composition comprises 20 to 45% by weight of ticagrella as an active ingredient; 20 to 45% by weight of D-mannitol as a soluble excipient; 10 to 30% by weight of microcrystalline cellulose as an insoluble excipient; 2 to 6% by weight of croscarmellose sodium as a disintegrant; And 0.5 to 3% by weight of hydroxypropylcellulose as a binder.

In the production process of the present invention, the drying step may be a drying at 50 to 70 ° C.

In the manufacturing method of the present invention, the drying may be performed so that the water content measured by LOD (Loss on Dry) is less than 2%.

The pharmaceutical composition comprising the ticagrella of the present invention as an active ingredient is a preparation for improving the solubility of ticagrella known as a poorly soluble drug, in which the active ingredient is released in an amount of 90% or more within 30 minutes to 90 minutes, The pharmacokinetic results can be obtained and the formulation can be developed to increase the compliance of patients.

FIG. 1 shows a dissolution test result of drugs according to an embodiment of the present invention.
2 shows a dissolution test result of a drug at pH 4.0 according to an embodiment of the present invention.
Figure 3 shows the dissolution profile of the drug at pH 6.8 according to one embodiment of the present invention.
Fig. 4 shows the dissolution test results of the drug at pH 7.0 (purified water) according to one embodiment of the present invention.

Below, The present invention will be described in more detail by way of examples. It is to be understood by those skilled in the art that these embodiments are merely illustrative of the present invention and that the scope of the present invention is not construed as being limited by these embodiments.

Comparative Example 1

90 mg of brilliant tablets (AstraZeneca, Lot No. HACC) containing 90 mg of the main component ticagrella were purchased.

Comparative Example 2 and Examples 1 to 3

Comparative Example 2 and Examples 1 to 3 were produced according to the following procedure according to the components and amounts of the following [Table 1]. The composition of Comparative Example 2 was the same as that of Example 1 of Korean Patent No. 10-1539467.

1) Tikageler (active ingredient) was sieved through a 30 mesh screen.

2) Sieve of step 1), D-mannitol (soluble excipient) and croscarmellose (disintegrant) were mixed in this order, and the mixture was sieved with a 20 mesh screen.

3) Microcrystalline cellulose (insoluble excipient) was added to the granules obtained in the step 2) and mixed.

4) Hydroxypropylcellulose (binder) was slowly added dropwise to about 30 purified water while dissolving to prepare a binding solution.

5) The coupling solution of step 4) was added dropwise to the mixture of step 3), and fed to a speed mixer.

6) The granules of step 5) were dried at 60 or more, and the dried material was dried with a Quadro Comil 050G screen.

7) Magnesium stearate (lubricant) was mixed with the sizing product of the step 6) to perform a lubrication process.

8) Granulation obtained through the above-mentioned sliding process was tableted and coated to complete an oral dosage form.

Ingredients Comparative Example 2 Example 1 Example 2 Example 3 Tikagueler 90 90 90 60 D-mannitol 126 130.5 126 126 Calcium hydrogen dihydrogen phosphate 63 - - 63 Microcrystalline cellulose - 63 63 - Starch glycolate sodium 9 - - - Sodium croscarmellose sodium - 9 9 9 Hydroxypropylcellulose 9 4.5 9 9 Magnesium stearate 3 3 3 3 Tablet weight (mg) 300 300 300 300

EXPERIMENTAL EXAMPLE 1. EXAMPLES AND COMPARATIVE EXAMPLES Evaluation

According to the second method (paddle method) of Examples 1 to 3 and Comparative Examples 1 and 2 of the general dissolution test described in the Pharmacopoeia General Test Methods, 900 mL of a dissolution test liquid prepared by mixing purified water and 80% of polysorbate 80% After elution at 50 rpm, the elution results of the tikageler were confirmed, and the results are shown in Fig.

Specifically, in Comparative Example 1 which is a commercially available ticagrella product, the 5-minute dissolution rate was 62.3% and the 30-minute dissolution rate was 91.2%, and in Comparative Example 2, the 5-minute dissolution rate was 27.1% and the 30-minute dissolution rate was 65.4 %, 5 minutes, and 30 minutes, respectively.

Examples 1 to 3 were prepared using croscarmellose sodium, which had the best disintegration effect on the formulation as a result of screening to select the optimal disintegrant.

In the case of Example 3, only the disintegrant was changed to croscarmellose sodium instead of sodium starch glycolate in the composition of Comparative Example 2. As a result of the dissolution test, the 5-minute dissolution rate was 42.6% Minute dissolution rate was 64.7%, which was not different from Comparative Example 2.

In the case of Example 2, the calcium phosphate dihydrate was changed to microcrystalline cellulose as an insoluble excipient in the composition of Example 3, and the change of the dissolution rate was confirmed. As a result, the dissolution rate at 5 minutes was 44.6% , And the dissolution rate at 30 minutes was 96.6%, which was significantly improved as compared with Comparative Examples 1 and 2.

In the case of Example 1, the ratio of the binder (hydroxypropylcellulose) in the composition of Example 2 was reduced. As a result of the dissolution test, the 5-minute dissolution rate was 62.3%, similar to Comparative Example 1, %, Which was significantly improved as compared with Comparative Example 1, and the optimum composition was found.

Experimental Example 2. Evaluation of elution at pH 4.0

The dissolution rates at pH 4.0 of Example 1 and Comparative Example 1 in which the elution effect was the best in the above experiment were confirmed. Specifically, the elution was carried out at a paddle rotation rate of 50 rpm in 900 mL of a dissolution test solution containing 1% of polysorbate 80% and acetic acid buffer solution of pH 4.0 according to Method 2 of the General Test Methods dissolution assay described in Korean Pharmacopoeia, The results of elution of ticagrella were confirmed, and the results are shown in Fig.

As a result of the experiment, the dissolution rate at 5 minutes was similar to that of Comparative Example 1 and Example 1 at 63.1% and 65.3%, respectively, whereas the dissolution rate at 45 minutes was 86% in Comparative Example 1, %, Which is significantly higher than that of Comparative Example 1.

Experimental Example 3. Evaluation of elution at pH 6.8

The dissolution rate at pH 6.8 of Example 1 and Comparative Example 1 was confirmed. Specifically, the elution was carried out in 900 mL of a dissolution test solution containing 1% of polysorbate 80 and phosphoric acid buffer solution of pH 6.8 according to Method 2 of the General Test Methods dissolution test described in Korean Pharmacopoeia General Test Methods at a rotation speed of 50 rpm, The results of elution of ticagrella were confirmed, and the results are shown in Fig.

As a result, the dissolution rate at 5 minutes was 56% and 56.3% in Comparative Example 1 and Example 1, respectively, but the dissolution rate at 90 minutes was 75.9% in Comparative Example 1, whereas 94.2 %, Which is significantly higher than that of Comparative Example 1.

Experimental Example 4. Evaluation of elution at pH 7.0

The dissolution rates of the above Example 1 and Comparative Example 1 at pH 7.0 were confirmed. Specifically, according to Method 2 of the General Test Methods dissolution test described in the Korean Pharmacopoeia, the elution was carried out at a paddle rotation speed of 50 rpm in 900 mL of a dissolution test liquid obtained by mixing purified water and 80% of polysorbate 80%, and elution of tikageler The results were confirmed, and the results are shown in FIG.

As a result, the dissolution rate at 5 minutes was similar to that of Comparative Example 1 and Example 1 at 61.3% and 62.3%, respectively. The dissolution rate at 30 minutes was 88.2% for Comparative Example 1, whereas 97.2% %, Which is significantly higher than that of Comparative Example 1.

Claims (21)

Comprising as an active ingredient tikageler or a salt thereof and one or more pharmaceutical excipients,
wherein the elution profile shows that at least 90% of the total weight of the active ingredient elutes at 30 minutes to 90 minutes after the start of the test in the buffer solution of pH 4.0 to pH 7.0.
The method according to claim 1,
Wherein the dissolution test is carried out at 37 占 0.5 占 폚, 1% polysorbate 80 solution, 50 rpm according to Korean Pharmacopoeia dissolution test method 2 (paddle method).
The method according to claim 1,
The pharmaceutical composition can be used for the dissolution test
(a) 90% or more of the total weight of tikageler is eluted at 45 minutes after the start of the test when the pH of the buffer solution is 4.0;
(b) 90% or more of the total weight of tikageler is eluted 90 minutes after the start of the test when the pH of the buffer solution is 6.8; Also
(c) a pH of the buffer solution is 7.0, and at least 90% of the total weight of the ticagrella is eluted at 30 minutes after the initiation of the test.
The method according to claim 1,
Wherein the pharmaceutical excipient is at least one selected from the group consisting of D-mannitol, microcrystalline cellulose, croscarmellose sodium, hydroxypropylcellulose, and glidant.
5. The method of claim 4,
Wherein the mixture of D-mannitol and microcrystalline cellulose is comprised between 30 and 70 wt% of the total weight of the composition.
5. The method of claim 4,
Wherein the D-mannitol comprises 20 to 45 wt% of the total weight of the composition.
5. The method of claim 4,
Wherein the microcrystalline cellulose is comprised between 10 and 30 wt% of the total weight of the composition.
5. The method of claim 4,
Wherein said croscarmellose sodium is comprised between 1 and 6% by weight of the total weight of the composition.
5. The method of claim 4,
Wherein the hydroxypropylcellulose comprises 0.5 to 3% by weight of the total weight of the composition.
5. The method of claim 4,
Wherein the lubricant is selected from the group consisting of magnesium stearate, sodium stearyl fumarate, talc, stearic acid, palmitic acid, calcium stearate, carnauba wax, hydrogenated vegetable oil, mineral oil, polyethylene glycol and silicon dioxide Lt; RTI ID = 0.0 > 1, < / RTI >
5. The method of claim 4,
Wherein the lubricant comprises 0.5 to 3 wt% of the total weight of the composition.
20 to 45% by weight of ticagrella as active ingredient;
20 to 45% by weight of D-mannitol;
10 to 30% by weight of microcrystalline cellulose;
2 to 6% by weight sodium croscarmellose sodium; And
0.5 to 3% by weight of hydroxypropyl cellulose.
13. The method of claim 12,
Wherein said pharmaceutical composition further comprises 0.5 to 3% by weight of a lubricant.
14. The method of claim 13,
Wherein the lubricant is selected from the group consisting of magnesium stearate, sodium stearyl fumarate, talc, stearic acid, palmitic acid, calcium stearate, carnauba wax, hydrogenated vegetable oil, mineral oil, polyethylene glycol and silicon dioxide Lt; RTI ID = 0.0 > 1, < / RTI >
13. The method of claim 12,
Wherein the pharmaceutical composition exhibits an elution profile in which at least 90% of the total weight of the active ingredient is eluted at 30 minutes to 90 minutes after the start of the test in the elution test in the buffer solution of pH 4.0 to pH 7.0. .
16. The method of claim 15,
Wherein the dissolution test is carried out at 37 占 0.5 占 폚, 1% polysorbate 80 solution, 50 rpm according to Korean Pharmacopoeia dissolution test method 2 (paddle method).
17. The method according to any one of claims 12 to 16,
The pharmaceutical composition can be used for the dissolution test
(a) 90% or more of the total weight of tikageler is eluted at 45 minutes after the start of the test when the pH of the buffer solution is 4.0;
(b) 90% or more of the total weight of tikageler is eluted 90 minutes after the start of the test when the pH of the buffer solution is 6.8; Also
(c) a pH of the buffer solution is 7.0, and at least 90% of the total weight of the ticagrella is eluted at 30 minutes after the initiation of the test.
Mixing and sieving the tikageler, the excipient and the disintegrant as active ingredients;
Mixing the sieved mixture with a binder, and granulating the mixture;
Drying and granulating the granules;
Mixing the sizing material with a lubricant; And
And shaping the granulated product through the gliding process.
19. The method of claim 18,
The pharmaceutical composition comprises 20 to 45% by weight of ticagrella as an active ingredient; 20 to 45% by weight of D-mannitol as a soluble excipient; 10 to 30% by weight of microcrystalline cellulose as an insoluble excipient; 2 to 6% by weight of croscarmellose sodium as a disintegrant; And 0.5 to 3% by weight of hydroxypropylcellulose as a binder.
19. The method of claim 18,
Wherein the drying step is performed at a temperature of 50 to 70 캜.
19. The method of claim 18,
Wherein the drying step is performed so that the measured water content by LOD (Loss on Dry) is 2% or less.

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