KR102376010B1 - Cored tablet comprising aspirin and ticagrelor - Google Patents

Abstract

The present invention provides an inner nuclear layer comprising aspirin or a pharmaceutically acceptable salt thereof as an active ingredient; And it relates to a core-coated tablet complex formulation comprising an outer layer comprising a two-layer structure of an immediate-release part and a sustained-release part, including tikageler or a pharmaceutically acceptable salt thereof, surrounding the surface of the inner core layer.

Description

Combination formulation containing aspirin and ticagrelor {CORED TABLET COMPRISING ASPIRIN AND TICAGRELOR}

The present invention relates to a core tablet combination formulation comprising aspirin and ticagrelor.

Ticagrelor (trade name Brilinta®) is represented by the following formula, and the chemical name is (1S,2S,3R,5S)-3-[7-[[(1R,2S)-2-(3,4-di Fluorophenyl)cyclopropyl]amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxye A compound that is oxy)cyclopentane-1,2-diol, which is being used as an antithrombotic agent:

[Formula]

Formulations containing ticagrelor as an active ingredient are mostly absorbed in the small intestine within about 2 hours after oral administration, and have a short half-life of 6 to 13 hours, which is inconvenient to take twice a day. In addition, patients taking ticagrelor should be administered aspirin in combination as a maintenance dose (75-150 mg).

Therefore, while minimizing the interaction between ticagrelor and aspirin, there is a need for research on novel combination formulations to maximize each drug's efficacy.

Korean Patent Publication No. 10-2016-0012706 (2016.02.03.)

The present invention provides a novel combination formulation for maximizing each drug effect while minimizing the interaction between ticagrelor and aspirin, comprising: an inner core layer comprising aspirin or a pharmaceutically acceptable salt thereof as an active ingredient; And it is intended to provide a core-coated tablet composite formulation comprising an outer layer comprising a two-layer structure of a sustained-release portion and an immediate-release portion, including tikageler or a pharmaceutically acceptable salt thereof, surrounding the surface of the inner core layer.

However, the technical problem to be achieved by the present invention is not limited to the above-mentioned problems, and other problems not mentioned will be clearly understood by those skilled in the art from the following description.

The present invention provides an inner nuclear layer comprising aspirin or a pharmaceutically acceptable salt thereof as an active ingredient; And it provides a core-coated tablet composite formulation comprising an outer layer comprising a two-layer structure of a sustained-release part and an immediate-release part, including tikageler or a pharmaceutically acceptable salt thereof, surrounding the surface of the inner core layer.

The inner core layer may be coated with an enteric polymer.

60% to 80% by weight of aspirin or a pharmaceutically acceptable salt thereof, based on the total weight of the inner nuclear layer; 10% to 30% by weight of microcrystalline cellulose; 1% to 10% by weight of croscarmellose sodium; 0.1% to 1% by weight of colloidal silicon dioxide; and 0.1 wt% to 1 wt% of magnesium stearate.

The weight ratio of the sustained-release portion and the immediate-release portion may be 50:50 to 30:70.

With respect to the total weight of the sustained-release portion, the content of the first tikageler or a pharmaceutically acceptable salt thereof included in the sustained-release portion is 35% to 45% by weight, and with respect to the total weight of the immediate-release portion, the immediate-release portion The content of the included second tikageler or a pharmaceutically acceptable salt thereof may be 20% by weight to 30% by weight.

The sustained release portion may contain hypromellose as a release-controlling polymer.

Based on the total weight of the sustained-release portion, 35 to 45% by weight of the first ticagrelor or a pharmaceutically acceptable salt thereof; 35% to 45% by weight of microcrystalline cellulose; 1 wt% to 10 wt% of hydroxypropylcellulose; 1 wt% to 10 wt% of anhydrous calcium phosphate; 5% to 15% by weight of hypromellose; and 1 wt% to 10 wt% of magnesium stearate.

Based on the total weight of the immediate release portion, 20% by weight to 30% by weight of a second ticagrelor or a pharmaceutically acceptable salt thereof; 20% to 30% by weight of mannitol; 35% to 45% by weight of microcrystalline cellulose; 1 wt% to 10 wt% of hydroxypropylcellulose; 1% to 10% by weight of croscarmellose sodium; and 1 wt% to 10 wt% of magnesium stearate.

When the core tablet combination formulation is stored for 8 weeks at 40° C. and 75% relative humidity, the individual related substances of ticagrelor are maintained at 0.2 wt% or less, and the total related substances are maintained at 0.5 wt% or less, and individual softening of aspirin Substances may be maintained at 2.0 wt% or less and total related substances at 3.0 wt% or less.

In the case of dissolution test in a buffer solution with 0.1N HCl:0.2M volume ratio = 3:1 for the core tablet combination formulation, at least 80% of the total weight of aspirin and 70% of the total weight of ticagrelor at 120 minutes after the start of the test It can represent a dissolution profile that elutes more than %.

The core-coated tablet combination formulation may be orally administered once a day.

In one embodiment of the present invention, (a) preparing an inner nuclear layer comprising aspirin or a pharmaceutically acceptable salt thereof as an active ingredient; (b) tableting the sustained-release portion containing the first ticagrelor or a pharmaceutically acceptable salt thereof, and then inserting the inner core layer prepared in step (a) into the compressed sustained-release portion; and (c) tableting the immediate-release portion containing the second ticagrelor or a pharmaceutically acceptable salt thereof, and then combining the compressed immediate-release portion with the sustained-release portion into which the inner core layer is inserted in step (b). It provides a method for manufacturing a core-coated tablet combination formulation comprising the.

The core-coated tablet combination formulation according to the present invention comprises: an inner core layer comprising aspirin or a pharmaceutically acceptable salt thereof as an active ingredient; And surrounding the surface of the inner core layer, comprising a ticagrelor or a pharmaceutically acceptable salt thereof, characterized in that it consists of an outer layer consisting of a two-layer structure of a sustained-release portion and an immediate-release portion, the ticagrelor contained in the outer layer maximized the convenience of taking by increasing both the initial release amount and the release duration from the small intestine, and aspirin contained in the inner nuclear layer was released from the intestine without acting on the stomach. Therefore, there is an advantage that can minimize the side effects caused by the interaction between ticagrelor and aspirin, and it can improve stability.

1 is a graph showing the dissolution rate of aspirin in the aspirin enteric inner core tablets prepared in Examples 1 to 3;
2 is a graph comparing the dissolution rate of aspirin in the combination formulations prepared in Examples 4 to 6;
Figure 3 is a graph comparing the dissolution rate of ticagrelor in the composite formulations prepared in Examples 4-6.

While the present inventors were researching on a novel combination formulation containing aspirin and ticagrelor, through formulation as a cored tablet combination formulation, the interaction between ticagrelor and aspirin was minimized, while maximizing each drug efficacy and improving stability It was confirmed that it can be done, and the present invention was completed.

Hereinafter, the present invention will be described in detail.

Combination tablet formulation

The present invention provides an inner nuclear layer comprising aspirin or a pharmaceutically acceptable salt thereof as an active ingredient; And it provides a core-coated tablet composite formulation comprising an outer layer comprising a two-layer structure of a sustained-release part and an immediate-release part, including tikageler or a pharmaceutically acceptable salt thereof, surrounding the surface of the inner core layer.

First, the core-coated tablet combination formulation according to the present invention includes an inner core layer containing aspirin or a pharmaceutically acceptable salt thereof as an active ingredient.

The inner core layer includes aspirin or a pharmaceutically acceptable salt thereof, but refers to a layer surrounded by an outer layer to be described later.

Aspirin or a pharmaceutically acceptable salt thereof contained in the inner nuclear layer corresponds to a drug that acts as an antipyretic, analgesic, and anti-inflammatory that requires co-administration with ticagrelor or a pharmaceutically acceptable salt thereof, which will be described later. The aspirin or a pharmaceutically acceptable salt thereof, aspirin is a substance with low gastrointestinal absorption, and when decomposed in the stomach, liberates into acetic acid and injures the stomach.

60% to 80% by weight of aspirin or a pharmaceutically acceptable salt thereof, based on the total weight of the inner nuclear layer; 10% to 30% by weight of microcrystalline cellulose; 1% to 10% by weight of croscarmellose sodium; 0.1% to 1% by weight of colloidal silicon dioxide; and 0.1 wt% to 1 wt% of magnesium stearate.

Specifically, the microcrystalline cellulose serves as a filler, and when the content is less than 10% by weight, there is a problem due to the difficulty in controlling the tablet weight and tableting hardness, and when it exceeds 30% by weight, the weight and volume of the inner core tablet Due to the increase, there are problems in tableting with the core-coated tablet and taking the tablet according to the increase in tablet size. In addition, the sodium croscarmellose is intended to act as a disintegrant, and when the content is less than 1% by weight, the dissolution rate of aspirin is significantly lowered, and when it exceeds 10% by weight, the dissolution rate of aspirin is further increased There is a limit that cannot be increased more than that. In addition, the colloidal silicon dioxide is intended to act as a lubricant, and when the content is less than 0.1% by weight, there is a problem due to the occurrence of sticking during tableting, and when it exceeds 1% by weight, binding of the tablet There are problems due to deterioration of properties and weakening of hardness. In addition, the magnesium stearate is intended to act as a lubricant, and when the content is less than 0.1% by weight, there is a problem due to the occurrence of sticking during tableting, and when it exceeds 1% by weight, disintegration time and dissolution There is a problem with the delay.

Since the inner core layer is coated with an enteric polymer, acetic acid can be released from the intestine without acting on the stomach. Specifically, the enteric polymer may use a known enteric polymer, and preferably may include methacrylic acid copolymer Type C (Methacrylic Acid Copolymer Type C). At this time, methacrylic acid copolymer Type C (Methacrylic Acid Copolymer Type C) is an aqueous acrylic enteric polymer that is well soluble in water, and can be homogeneously dissolved in water and dispersed in a 10% solid content. In addition, it plays a role in allowing the drug to be released at pH 5.5-7.5.

Next, the core-coated tablet composite formulation according to the present invention includes an outer layer comprising a tikageler or a pharmaceutically acceptable salt thereof, surrounding the surface of the inner core layer, and having a two-layer structure of a sustained-release part and an immediate-release part.

The outer layer includes a tikageler or a pharmaceutically acceptable salt thereof, but refers to a layer entirely surrounding the surface of the inner core layer.

Tikageler or a pharmaceutically acceptable salt thereof contained in the outer layer corresponds to a drug having an antithrombotic action. However, since it has a short half-life of 6 to 13 hours, it is inconvenient to take it twice a day, so it is necessary to increase the release duration.

The outer layer may be made of a two-layer structure of the sustained-release portion and the immediate-release portion, thereby maximizing the convenience of taking ticagrelor by increasing both the initial release amount and the release duration in the small intestine.

The sustained release portion includes the first ticagrelor or a pharmaceutically acceptable salt thereof, and may enable sustained release of the ticagrelor.

The sustained release portion, based on the total weight, the first ticagrelor or a pharmaceutically acceptable salt thereof 35% to 45% by weight; 35% to 45% by weight of microcrystalline cellulose; 1 wt% to 10 wt% of hydroxypropylcellulose; 1 wt% to 10 wt% of anhydrous calcium phosphate; 5% to 15% by weight of hypromellose; and 1 wt% to 10 wt% of magnesium stearate.

Specifically, the microcrystalline cellulose serves as a filler, and when the content is less than 35% by weight, there is a problem due to the difficulty in controlling the tablet weight and tableting hardness, and when it exceeds 45% by weight, the tablet size increases There are difficulties in taking it. In addition, the hydroxypropyl cellulose serves as a binder, and when the content is less than 1% by weight, there is a problem due to sticking or capping during tableting, and when it exceeds 10% by weight, There is a problem in delaying the disintegration of the tablet. In addition, the anhydrous calcium phosphate serves as an excipient and a filler, and the anhydrous calcium phosphate has a high density and when the content is less than 1% by weight, there is a problem that the tablet floats during the dissolution test, and when it exceeds 10% by weight There are problems in that tablet weight increases and hardness does not increase any more. In addition, the magnesium stearate is intended to act as a lubricant, and when the content is less than 1% by weight, there is a problem due to the occurrence of sticking during tableting, and when it exceeds 10% by weight, disintegration time and dissolution There is a problem with the delay.

On the other hand, the sustained-release part is a release-controlling polymer, which does not use a hydrophobic lipid excipient and may contain hypromellose. There is a problem in that it is difficult to release a certain amount of , and when it exceeds 15% by weight, the release amount of the main component ticagrelor is lowered and there is a problem according to the lowering of the expression of the drug in the body (Cmax, AUC)). In the present invention, hypromellose K100 was used.

The immediate release portion is to include the first ticagrelor or a pharmaceutically acceptable salt thereof, and may enable immediate release of the ticagrelor.

Based on the total weight of the immediate release portion, 20% by weight to 30% by weight of a second ticagrelor or a pharmaceutically acceptable salt thereof; 20% to 30% by weight of mannitol; 35% to 45% by weight of microcrystalline cellulose; 1 wt% to 10 wt% of hydroxypropylcellulose; 1% to 10% by weight of croscarmellose sodium; and 1 wt% to 10 wt% of magnesium stearate.

Specifically, the mannitol serves as a filler, and when the content is less than 20% by weight, there is a difficulty in controlling the tablet weight and tableting hardness, and when it exceeds 30% by weight, it is difficult to take due to an increase in the tablet size. there is. In addition, the microcrystalline cellulose also serves as a filler, and when the content is less than 35% by weight, there is a difficulty in controlling the tablet weight and tableting hardness, and when it exceeds 45% by weight, it is difficult to take due to an increase in the tablet size. there is. In addition, the hydroxypropyl cellulose serves as a binder, and when the content is less than 1% by weight, there is a problem due to sticking or capping during tableting, and when it exceeds 10% by weight, There is a problem in delaying the disintegration of the tablet. In addition, the croscarmellose sodium is to serve as a disintegrant, and when the content is less than 1% by weight, there is a problem that the dissolution rate of ticagrelor is greatly lowered, and when it exceeds 10% by weight, ticagrelor There is a limit that cannot further increase the dissolution rate of In addition, the magnesium stearate is intended to act as a lubricant, and when the content is less than 1% by weight, there is a problem due to the occurrence of sticking during tableting, and when it exceeds 10% by weight, disintegration time and dissolution There is a problem with the delay.

In this case, the weight ratio of the sustained-release portion and the immediate-release portion may be 50:50 to 30:70.

Per 1 tablet of the core-coated tablet combination formulation, the aspirin or a pharmaceutically acceptable salt thereof may be 75 mg to 150 mg, and the ticagrelor or a pharmaceutically acceptable salt thereof may be 150 mg to 250 mg .

When the core tablet combination formulation is stored for 8 weeks at 40° C. and 75% relative humidity, the individual related substances of ticagrelor are 0.2% by weight or less (preferably, 0.07% by weight or less), and the total related substances are 0.5% by weight or less (preferably 0.1 wt% or less), individual related substances of aspirin are 2.0 wt% or less (preferably 0.1 wt% or less), and total related substances are 3.0 wt% or less (preferably 0.2 wt% or less) ) can be maintained.

In the case of dissolution test in a buffer solution with 0.1N HCl:0.2M volume ratio = 3:1 for the core tablet combination formulation, 10% or more of the total weight of aspirin at 10, 30, and 120 minutes after the start of the test ( Preferably, 20% or more), 50% or more (preferably 60% or more), and 80% or more (preferably 90% or more) may represent a dissolution profile that elutes.

On the other hand, in the dissolution test in a buffer solution of 0.1N HCl:0.2M volume ratio = 3:1 for the core tablet combination formulation, the total weight of ticagrelor at 1 hour, 12 hours, and 24 hours after the start of the test, respectively 20% or more), 50% or more (preferably 55% or more), and 70% or more (preferably 75% or more) may represent a dissolution profile. Therefore, it is possible to increase both the initial release amount and the release duration of ticagrelor.

As the core tablet combination formulation consists of a two-layer structure of the sustained-release part and the immediate-release part in the outer layer containing the ticagrelor and its pharmaceutically acceptable salt, it is possible to increase both the initial release amount and the release duration in the small intestine. Bar, it is possible to exhibit sufficient drug effect even with oral administration once a day.

Method for manufacturing the co-packaged tablet formulation

The present invention comprises the steps of (a) preparing an inner nuclear layer comprising aspirin or a pharmaceutically acceptable salt thereof as an active ingredient; (b) tableting the sustained-release portion containing the first ticagrelor or a pharmaceutically acceptable salt thereof, and then inserting the inner core layer prepared in step (a) into the compressed sustained-release portion; and (c) tableting the immediate-release portion containing the second ticagrelor or a pharmaceutically acceptable salt thereof, and then combining the compressed immediate-release portion with the sustained-release portion into which the inner core layer is inserted in step (b). It provides a method for manufacturing a core-coated tablet combination formulation comprising the.

In the manufacturing method of the core-coated tablet combination formulation according to the present invention, the "inner core layer", "sustained release part (first ticagrelor sustained release part)" and "immediate release part (second ticagrelor immediate release part)" have been described above for Therefore, redundant description will be omitted.

On the other hand, after preparing the inner core layer in step (a), it may further comprise the step of coating it with an enteric polymer. At this time, since "coating with an enteric polymer" has also been described above, a redundant description will be omitted.

In addition, tableting or binding in steps (b) and (c) can be performed using a known nucleated tablet press. Specifically, Autotab-200TR manufactured by Ichihashiseiki was used in the present invention.

As described above, the core-coated tablet combination formulation according to the present invention comprises: an inner core layer comprising aspirin or a pharmaceutically acceptable salt thereof as an active ingredient; And surrounding the surface of the inner core layer, comprising a ticagrelor or a pharmaceutically acceptable salt thereof, characterized in that it consists of an outer layer consisting of a two-layer structure of a sustained-release portion and an immediate-release portion, the ticagrelor contained in the outer layer maximized the convenience of taking by increasing both the initial release amount and the release duration from the small intestine, and aspirin contained in the inner nuclear layer was released from the intestine without acting on the stomach. Therefore, there is an advantage that can minimize the side effects caused by the interaction between ticagrelor and aspirin, and it can improve stability.

Hereinafter, preferred examples are presented to help the understanding of the present invention. However, the following examples are only provided for easier understanding of the present invention, and the contents of the present invention are not limited by the following examples.

[Example]

Examples 1-3

Aspirin enteric inner core tablets were prepared according to the composition shown in Table 1 below.

Specifically, aspirin, microcrystalline cellulose and croscarmellose sodium were sieved through 30 mesh and mixed in a bin for 20 minutes. After mixing, colloidal silicon dioxide and magnesium stearate were sieved with 20 mesh and mixed in a bin for 5 minutes. This mixture was compressed in a tableting machine to prepare uncontained aspirin tablets containing 100 mg of aspirin per tablet. Then, after uniformly dissolving Methacrylic Acid Copolymer Type C, talc, titanium oxide, triethyl citrate and sodium lauryl sulfate, it is added to aspirin raw tablets until the total weight is 155 mg per tablet. By enteric coating, aspirin enteric inner core tablets were prepared.

Ingredient name Example 1 Example 2 Example 3 aspirin aspirin 100 100 100 Microcrystalline Cellulose 38 34 30 Croscarmellose Sodium 0 4 8 colloidal silicon dioxide One One One Magnesum Stearate One One One aspirin raw tablet total weight 140 140 140 enteric coating Methacrylic acid copolymer type C 6.5 6.5 6.5 talc 5 5 5 titanium oxide 2 2 2 triethyl citrate 0.8 0.8 0.8 Sodium Lauryl Sulfate 0.7 0.7 0.7 Total weight of enteric coating 15 15 15 Aspirin enteric inner core tablet total weight 155 155 155

First, in the aspirin enteric-resistant core tablets prepared in Examples 1 to 3, acid resistance was evaluated. Specifically, as a result of performing acid resistance evaluation for 2 hours at a speed of 100 rpm in a basket containing 750 ml of 0.1N HCl, it is confirmed that all of Examples 1 to 3 meet the acid resistance standards (Table 2). On the other hand, as a control, 100 mg of Hanmi Aspirin Enteric Tablet, a reference drug published by the Ministry of Food and Drug Safety, was used.

control Example 1 Example 2 Example 3 standard Acid resistance (%) 1.8% 1.9% 2.1% 1.90% less than 10%

Next, in the aspirin enteric inner core tablets prepared in Examples 1 to 3, the dissolution rate of aspirin was evaluated. After 250 mL of 0.2M trisodium phosphate was put into the basket on which acid resistance evaluation was performed, dissolution rate evaluation was performed at a speed of 100 rpm, and the results are shown in FIG. 1 .

As shown in FIG. 1 , Examples 1 to 3 all had excellent aspirin dissolution rates. In particular, as in Examples 2 to 3, when croscarmellose sodium was used to prepare uncoated aspirin tablets, the aspirin dissolution rate was particularly excellent. It is confirmed that it is at the same level as that of the control group.

Examples 4-6

Composite tablets were prepared according to the composition shown in Table 3 below.

Specifically, aspirin enteric inner core tablets were prepared according to Examples 1 to 3.

Next, after sieving the first ticagrelor and microcrystalline cellulose through a 20 mesh, they were mixed in a bin for 20 minutes, and then a binding solution in which hydroxypropyl cellulose was dissolved in purified water was added and kneaded for 2 minutes to form granules. After sieving the formed granules, after drying at 60° C. for 4 hours, anhydrous calcium phosphate and hypromellose K100 were mixed well, and then magnesium stearate was mixed, whereby the first tikageler sustained-release part was tableted into a single-layer tablet. An aspirin enteric inner core tablet was inserted here.

Next, after sieving the second ticagrelor, D-mannitol, microcrystalline cellulose and croscarmellose sodium through 20 mesh, a binding solution in which hydroxypropyl cellulose was dissolved in purified water was added and kneaded for 2 minutes to form granules. After sieving the formed granules, after drying at 60° C. for 4 hours, magnesium stearate was added and mixed to tablet the second ticagrelor immediate-release portion into a single-layer tablet, and then the ticagrelor sustained-release portion into which the aspirin inner core tablet was inserted was combined. .

At this time, tableting and binding were performed using a core tablet press (Autotab-200TR manufactured by Ichihashiseiki).

Comparative Example 1

According to the composition shown in Table 3 below, a composite formulation consisting only of an immediate-release portion and a sustained-release portion was prepared.

Specifically, after sieving the first ticagrelor and microcrystalline cellulose through a 20 mesh, they were mixed in a bin for 20 minutes, and then a binding solution in which hydroxypropyl cellulose was dissolved in purified water was added and kneaded for 2 minutes to form granules. After sieving the formed granules, after drying at 60° C. for 4 hours, anhydrous calcium phosphate and hypromellose K100 were mixed well, and then magnesium stearate was mixed, whereby the first tikageler sustained-release part was tableted into a single-layer tablet.

Next, the second ticagrelor, aspirin, D-mannitol, microcrystalline cellulose and croscarmellose sodium were sieved through a 20 mesh, and then a binding solution in which hydroxypropyl cellulose was dissolved in purified water was added and kneaded for 2 minutes to form granules. After sieving the formed granules, after drying at 60° C. for 4 hours, magnesium stearate was added and mixed, aspirin and the second ticagrelor immediate-release part were compressed into a single-layer tablet, and then the ticagrelor sustained-release part was combined.

Comparative Examples 2-3

According to the composition shown in Table 3 below, a core-coated tablet composite formulation in which the enteric coating was omitted was prepared.

Specifically, a core-coated tablet combination formulation was prepared in the same manner as in Examples 1 and 2, except that an uncoated aspirin tablet containing 100 mg of aspirin per tablet was applied instead of the aspirin enteric inner core tablet.

Ingredient name Comparative Example 1 Comparative Example 2 Comparative Example 3 Example 4 Example 5 Example 6 aspirin aspirin - 100 100 100 100 100 Microcrystalline Cellulose - 38 34 38 34 30 Croscarmellose Sodium - 0 4 0 4 8 colloidal silicon dioxide - One One One One One Magnesum Stearate - One One One One One aspirin raw tablet total weight - 140 140 140 140 140 enteric coating Methacrylic acid copolymer type C - - - 6.5 6.5 6.5 talc - - - 5 5 5 titanium oxide - - - 2 2 2 triethyl citrate - - - 0.8 0.8 0.8 Sodium Lauryl Sulfate - - - 0.7 0.7 0.7 Total weight of enteric coating - - - 15 15 15 Total weight of aspirin enteric inner nuclear layer - 140 140 155 155 155 1st tikageler
western 1st tikageler 110 110 110 110 110 110 Microcrystalline Cellulose 100 100 100 100 100 100 Hydroxypropyl Cellulose 5 5 5 5 5 5 Anhydrous calcium phosphate 15 15 15 15 15 15 Hypromellose K100 30 30 30 30 30 30 Magnesum Stearate 5 5 5 5 5 5 1st tikageler
Western Gross Weight 265 265 265 265 265 265 2nd Tikageler
quick release 2nd Tikageler 70 70 70 70 70 70 aspirin 100 - - - - - D-mannitol 76 76 76 76 76 76 Microcrystalline Cellulose 116 116 116 116 116 116 Hydroxypropyl Cellulose 7.8 7.8 7.8 7.8 7.8 7.8 Croscarmellose Sodium 6.2 6.2 6.2 6.2 6.2 6.2 Magnesum Stearate 4 4 4 4 4 4 2nd Tikageler
Total weight of immediate release 380 280 280 280 280 280 final Opadry 03B28796 20 20 20 20 20 20 gross weight 665 705 705 705 705 705

First, in the composite formulations prepared in Examples 4 to 6 and Comparative Examples 1 to 3, acid resistance was evaluated. Specifically, as a result of performing acid resistance evaluation for 2 hours at a speed of 100 rpm in a basket containing 750 ml of 0.1N HCl, it is confirmed that all of Examples 4 to 6 meet the acid resistance standards. On the other hand, Comparative Examples 1 to 3 are all cases in which the enteric coating is omitted, which is confirmed to be unsuitable for the acid resistance standard (Table 4).

Example 4 Example 5 Example 6 Comparative Example 1 Comparative Example 2 Comparative Example 3 standard Acid resistance (%) 1.9% 1.89% 1.91% 15.3% 13.1% 18.9% less than 10%

Next, in the combination formulations prepared in Examples 4 to 6 and Comparative Examples 1 to 3, the dissolution rate of aspirin and ticagrelor was evaluated. After 250 mL of 0.2M trisodium phosphate was put into the basket on which acid resistance evaluation was performed, dissolution rate evaluation was performed at a speed of 100 rpm, and the results are shown in FIGS. 2 and 3 , respectively.

As shown in Figure 2, Examples 4 to 6 all had excellent aspirin dissolution rates, but in particular, when croscarmellose sodium was used to prepare aspirin uncoated tablets as in Examples 5 to 6, the aspirin dissolution rate was particularly excellent ( It is confirmed that the level is equivalent to that of the control group).

As shown in Figure 3, it is confirmed that all of Examples 4 to 6 increased the initial release amount and release duration of ticagrelor.

Next, in the composite formulations prepared in Examples 4 to 6 and Comparative Examples 1 to 3, stability evaluation was performed under accelerated conditions. Specifically, PTP packaging (PVC/Aluminum) was carried out for stability evaluation for 8 weeks under accelerated conditions (40℃, 75% RH), and the content of individual related substances, other unknown related substances and total related substances for ticagrelor was measured, and the results are shown in Table 5.

Early Example 4 Example 5 Example 6 Comparative Example 1 Comparative Example 2 Comparative Example 3 standard Tikageler related substances (%) <0.01 <0.01 <0.01 <0.01 <0.01 <0.01 0.3% or less Other unknown related substances (%) <0.01 <0.01 <0.01 <0.01 <0.01 <0.01 0.2% or less Total related substances (%) <0.1 <0.1 <0.1 <0.1 <0.1 <0.1 0.5% or less Judgment fitness fitness fitness fitness fitness fitness Final judgment:% of total related substances after 4 weeks standard Tikageler related substances (%) 0.040 0.039 0.041 0.054 0.055 0.052 0.3% or less Other unknown related substances (%) 0.022 0.019 0.023 0.023 0.026 0.019 0.2% or less Total related substances (%) 0.062 0.058 0.064 0.077 0.081 0.071 0.5% or less Judgment fitness fitness fitness fitness fitness fitness Final judgment:% of total related substances after 8 weeks standard Tikageler related substances (%) 0.059 0.058 0.055 0.116 0.083 0.084 0.3% or less Other unknown related substances (%) 0.032 0.038 0.031 0.036 0.039 0.036 0.2% or less Total related substances (%) 0.091 0.096 0.086 0.152 0.122 0.12 0.5% or less Judgment fitness fitness fitness fitness fitness fitness Final judgment:% of total related substances

As shown in Table 5, in the combination formulations prepared in Examples 4 to 6, the results of stability evaluation for 8 weeks under accelerated conditions (40 ℃, 75% RH), individual related substances for ticagrelor, Since the content of other unknown related substances and total related substances hardly occurs, it is confirmed that the stability is excellent.

In addition, the contents of individual related substances, other unknown related substances and total related substances for aspirin were measured, and the results are shown in Table 6.

Early Example 4 Example 5 Example 6 Comparative Example 1 Comparative Example 2 Comparative Example 3 standard Aspirin related substances (%) <0.01 <0.01 <0.01 <0.01 <0.01 <0.01 2.0% or less Other unknown related substances (%) <0.01 <0.01 <0.01 <0.01 <0.01 <0.01 0.2% or less Total related substances (%) <0.1 <0.1 <0.1 <0.1 <0.1 <0.1 3.0% or less Judgment fitness fitness fitness fitness fitness fitness Final judgment:% of total related substances after 4 weeks standard Aspirin related substances (%) 0.071 0.071 0.072 0.122 0.075 0.077 2.0% or less Other unknown related substances (%) 0.079 0.089 0.086 0.084 0.083 0.081 0.2% or less Total related substances (%) 0.15 0.16 0.158 0.206 0.158 0.158 3.0% or less Judgment fitness fitness fitness fitness fitness fitness Final judgment:% of total related substances after 8 weeks standard Aspirin related substances (%) 0.084 0.087 0.082 0.216 0.126 0.124 2.0% or less Other unknown related substances (%) 0.083 0.091 0.094 0.111 0.101 0.099 0.2% or less Total related substances (%) 0.167 0.178 0.176 0.327 0.227 0.223 3.0% or less Judgment fitness fitness fitness fitness fitness fitness Final judgment:% of total related substances

As shown in Table 5, in the combination formulations prepared in Examples 4 to 6, stability evaluation was performed for 8 weeks under accelerated conditions (40° C., 75% RH). As a result, individual related substances for aspirin, other unknowns Since the content of related substances and total related substances hardly occurs, it is confirmed that the stability is excellent.

The description of the present invention described above is for illustration, and those of ordinary skill in the art to which the present invention pertains can understand that it can be easily modified into other specific forms without changing the technical spirit or essential features of the present invention. will be. Therefore, it should be understood that the embodiments described above are illustrative in all respects and not restrictive.

Claims (13)

an inner core layer comprising aspirin or a pharmaceutically acceptable salt thereof as an active ingredient; and
A core-coated tablet complex formulation comprising an outer layer surrounding the surface of the inner core layer, containing tikageler or a pharmaceutically acceptable salt thereof, and having a two-layer structure of a sustained-release part and an immediate-release part,
The inner core layer further comprises croscarmellose sodium, the inner core layer is coated with an enteric polymer, and 60 to 80 wt% of aspirin or a pharmaceutically acceptable salt thereof based on the total weight of the inner core layer weight%; Croscarmellose sodium is included in an amount of 1% to 10% by weight,
With respect to the total weight of the sustained-release portion, the content of the first tikageler or a pharmaceutically acceptable salt thereof included in the sustained-release portion is 35% to 45% by weight, and the second ticagrelor included in the immediate-release portion or The content of a pharmaceutically acceptable salt thereof is 20% to 30% by weight, characterized in that the core tablet combination formulation.
delete According to claim 1,
60% to 80% by weight of aspirin or a pharmaceutically acceptable salt thereof, based on the total weight of the inner nuclear layer; 10% to 30% by weight of microcrystalline cellulose; 1% to 10% by weight of croscarmellose sodium; 0.1% to 1% by weight of colloidal silicon dioxide; And 0.1 wt% to 1 wt% of magnesium stearate, characterized in that it comprises a core tablet combination formulation.
According to claim 1,
The weight ratio of the sustained-release portion and the immediate-release portion is 50:50 to 30:70, a core-coated tablet combination formulation.
delete According to claim 1,
The sustained release portion is a release-controlling polymer, characterized in that it contains hypromellose, a core-coated tablet combination formulation.
The method of claim 1,
Based on the total weight of the sustained-release portion, 35% to 45% by weight of the first ticagrelor or a pharmaceutically acceptable salt thereof; 35% to 45% by weight of microcrystalline cellulose; 1 wt% to 10 wt% of hydroxypropylcellulose; 1 wt% to 10 wt% of anhydrous calcium phosphate; 5% to 15% by weight of hypromellose; And Magnesium stearate 1% to 10% by weight, characterized in that it comprises a core tablet combination formulation.
According to claim 1,
Based on the total weight of the immediate release portion, 20% by weight to 30% by weight of the second ticagrelor or a pharmaceutically acceptable salt thereof; 20% to 30% by weight of mannitol; 35% to 45% by weight of microcrystalline cellulose; 1 wt% to 10 wt% of hydroxypropylcellulose; 1% to 10% by weight of croscarmellose sodium; And Magnesium stearate 1% to 10% by weight, characterized in that it comprises a core tablet combination formulation.
According to claim 1,
When the core tablet combination formulation is stored for 8 weeks at 40° C. and 75% relative humidity, the individual related substances of ticagrelor are maintained at 0.2 wt% or less, and the total related substances are maintained at 0.5 wt% or less, and individual softening of aspirin The core tablet combination formulation, characterized in that the content is maintained at 2.0 wt% or less and the total related substances at 3.0 wt% or less.
According to claim 1,
In the case of dissolution test in a buffer solution of 0.1N HCl:0.2M volume ratio = 3:1 for the core tablet combination formulation, it exhibits a dissolution profile in which 80% or more of the total weight of aspirin is eluted at 120 minutes after the start of the test to, a press-coated tablet combination formulation.
According to claim 1,
In the case of dissolution test in a buffer solution of 0.1N HCl:0.2M volume ratio = 3:1 for the core tablet combination formulation, it shows a dissolution profile in which at least 70% of the total weight of ticagrelor is eluted at 24 hours after the start of the test Characterized in that, the core tablet combination formulation.
According to claim 1,
The core-coated tablet combination formulation is characterized in that it is orally administered once a day, the core-coated tablet combination formulation.
(a) 60% to 80% by weight of aspirin or a pharmaceutically acceptable salt thereof based on the total weight of the inner nuclear layer as an active ingredient, and 1% to 10% by weight of croscarmellose based on the total weight of the inner nuclear layer After preparing an inner core layer further comprising sodium, coating the inner core layer with an enteric polymer to prepare an enteric inner core tablet;
(b) tabletting the sustained-release portion containing 35% to 45% by weight of the first ticagrelor or a pharmaceutically acceptable salt thereof with respect to the total weight of the sustained-release portion, and then the tableted sustained-release portion in the step (a) inserting the enteric inner core tablet prepared in and
(c) tableting the immediate-release portion containing 20% to 30% by weight of the second ticagrelor or a pharmaceutically acceptable salt thereof with respect to the total weight of the immediate-release portion, and then the tableted immediate-release portion and the (b) A method for manufacturing a core-coated tablet complex formulation comprising the step of combining the sustained-release portion into which the enteric-coated inner-core tablet prepared in the above step is inserted.

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