WO2024080736A1

WO2024080736A1 - Combination preparation comprising clopidogrel and ilaprazole

Info

Publication number: WO2024080736A1
Application number: PCT/KR2023/015614
Authority: WO
Inventors: 김동연; 정유석; 신재수; 이준연; 정형모; 이승현; 장우석; 이수헌
Original assignee: 일양약품주식회사
Priority date: 2022-10-12
Filing date: 2023-10-11
Publication date: 2024-04-18

Abstract

The present invention provides a feature related to a cored tablet combination preparation comprising clopidogrel or a pharmaceutically acceptable salt thereof and ilaprazole as active ingredients. The cored tablet combination preparation of the present invention can prevent or treat gastrointestinal side effects caused by the use of clopidogrel without inhibiting the efficacy of clopidogrel.

Description

Combination medication containing clopidogrel and ilaprazole

The present invention relates to a combination preparation containing clopidogrel and ilaprazole. Specifically, the combination preparation refers to a press-coated tablet combination preparation consisting of an inner core and an outer layer. More specifically, it relates to a press-coated tablet combination preparation consisting of an outer layer containing clopidogrel as an active ingredient and an inner core containing ilaprazole as an active ingredient.

Clopidogrel is an antithrombotic agent, specifically an antiplatelet agent, used for the prevention and treatment of vascular diseases such as arteriosclerosis, stroke, thrombosis, embolism, and myocardial infarction. Its chemical name is methyl (+)-(S)-α- It is (2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate.

Clopidogrel is an adenosinediphosphate (ADP) receptor antagonist known to play an important role in the formation of blood clots. It directly inhibits platelet aggregation that occurs when ADP binds to the receptor and activates the glycoprotein GPⅡb/Ⅲa receptor that amplifies platelet aggregation. Inhibits platelet aggregation.

The pharmacological action of clopidogrel is achieved by active metabolites formed in the liver after oral administration. This active metabolite irreversibly modifies the ADP receptor, preventing ADP from binding to the ADP receptor. Therefore, the effect of clopidogrel largely depends on the enzyme that metabolizes clopidogrel in the liver. Specifically, the enzymes that act in the formation of the active metabolite of clopidogrel in the liver are CYP1A and CYP2C19.

Clopidogrel has side effects that cause gastrointestinal problems such as stomach ulcers and gastrointestinal bleeding. To solve this problem, there are cases where it is prescribed in combination with PPI (Proton Pump Inhibitors, PPI) class drugs. Typically, PPI drugs increase the acidity of the stomach and are widely used in the treatment of gastroesophageal reflux disease, gastric ulcers, duodenal ulcers, etc., as well as bleeding peptic ulcers. P-CAB (Potassium Competitive Acid Blodker) class drugs, like PPI class drugs, are known to increase stomach acidity by suppressing gastric acid secretion. There are attempts to develop pharmaceutical compositions using P-CAB class drugs to prevent and treat gastrointestinal bleeding caused by taking antiplatelet drugs such as clopidogrel.

Specifically, Republic of Korea Patent Publication No. 10-2020-0024413 provides information on a pharmaceutical composition prepared with clopidogrel and tegoprazan in the form of pellets or granules. In addition, Korean Patent Publication No. 10-2021-0109479 describes a combination press-coated tablet using an inner core tablet containing tegoprazan as an active ingredient and an outer core containing clopidogrel as an active ingredient. However, the composition presented in the above patent contains an inner core tablet, which is a delayed-release tablet, containing primary, secondary, and tertiary coating layers containing tegoprazan as an active ingredient, and an outer layer containing the active ingredient clopidogrel manufactured using a wet granulation method. In the case of the currently commercially available K-Kep tablet (tegoprazan), it is an immediate-release tablet and it can be very difficult to determine bioequivalence when compared pharmaceutically with a delayed-release agent containing tegoprazan as an active ingredient. . Therefore, when compared to the combination formulation of the inner core tablet containing ilaprazole and the core tablet containing clopidogrel presented in the present invention, the above methods have a problem in that the manufacturing method is somewhat complicated.

The cored tablet combination formulation presented in the present invention is characterized by a rapid dissolution rate of the outer layer to ensure bioequivalence of the inner core tablet, which is a delayed-release agent. Specifically, the dissolution of clopidogrel from the outer layer containing clopidogrel as an active ingredient is 85% within 15 minutes. It indicates a dissolution rate of % or more.

In addition, compared to PPI class drugs, P-CAB class drugs have limitations in being selected as treatments for bleeding peptic ulcers due to the lack of research on the safety of long-term use and treatment of bleeding peptic ulcers.

Most PPI drugs (e.g. omeprazole, esomeprazole, pantoprazole, lansoprazole) are metabolized by CYP2C19 and inhibit CYP2C19. As a result, a series of studies have reported that the co-administration of clopidogrel and PPI drugs reduces the efficacy of clopidogrel by half. In particular, in the case of poor metabolizers with poor function due to a genetic defect in the CYP2C19 gene, the risk of cardiovascular disease is known to increase even if clopidogrel is taken alone. Taking PPI drugs that inhibit CYP2C19 is known to increase the risk of CYP2C19. There is concern that the efficacy of clopidogrel may decrease significantly due to increased inhibition.

Accordingly, in November 2009, the U.S. FDA warned that the anticoagulant effect of clopidogrel may be reduced by nearly half when administered in combination with omeprazole. Because of this risk, when co-administering clopidogrel and PPI drugs, it is generally recommended that the PPI be administered before breakfast and the clopidogrel be administered at a sufficient interval of 12 hours or more, such as before bedtime, resulting in poor patient compliance. .

Ilaprazole is a third-generation proton pump inhibitor, and its chemical name is 2-[[(4-methoxy-3-methyl)-2-pyridinyl]methylsulfinyl]-5-(1H-pyrrol-1-yl)-1H. -It is benzimidazole.

Ilaprazole is the only PPI drug with a pyrole ring structure and has a relatively long half-life, making it excellent for suppressing nocturnal acid secretion. Additionally, while other PPI drugs are metabolized by CYP2C19, ilaprazole is mostly metabolized non-enzymatically and is known to be partially metabolized by CYP3A4. Therefore, by administering the clopidogrel-ilaprazole combination drug developed in this study, gastrointestinal disorders caused by taking clopidogrel can be prevented and treated without inhibiting the efficacy of clopidogrel.

Republic of Korea Patent No. 10-1784001 proposes a pharmaceutical composition for oral administration containing an antiplatelet agent and an acid inhibitor. Specifically, the patent includes information on a composition of clopidogrel and a proton pump inhibitor. However, as described above, the composition proposed in the patent has limitations that do not take into account the problem that common PPI drugs are metabolized by CYP2C19 and inhibit the function of CYP2C19, thereby inhibiting the efficacy of clopidogrel. .

The purpose of the present invention is to provide a press-coated tablet combination preparation containing clopidogrel or a pharmaceutically acceptable salt thereof and ilaprazole as active ingredients.

The present invention provides an inner core tablet containing ilaprazole as an active ingredient; and a press-coated tablet combination preparation consisting of an outer layer containing clopidogrel or a pharmaceutically acceptable salt thereof as an active ingredient.

The combination preparation presented in the present invention can prevent or treat gastrointestinal disorders caused by taking clopidogrel without inhibiting the medicinal efficacy of clopidogrel when clopidogrel or a pharmaceutically acceptable salt thereof is administered as an active ingredient.

The combination preparation of the present invention contains 75 to 300 mg of clopidogrel or a pharmaceutically acceptable salt thereof as an active ingredient in the outer layer, and 10 to 20 mg of ilaprazole as an active ingredient in the inner core tablet, and the ilaprazole content in the inner core tablet is equal to the content of the inner core tablet. It is characterized in that it is 5 to 20% by weight of the net mass.

The inner core tablet of the combination preparation presented in the present invention contains ilaprazole as an active ingredient, and the inner core tablet is characterized as an enteric-coated tablet. Specifically, the enteric-coated tablet does not dissolve at low pH, such as the human stomach, and can be dissolved under conditions of pH 5.0 or higher, specifically pH 5.5 or higher.

It is difficult to ensure the stability of PPI drugs, including ilaprazole, in moisture and acidic conditions. Accordingly, enteric coating was applied to the inner core tablet containing ilaprazole as an active ingredient, and the stability of ilaprazole was secured by designing it to be released from the small intestine rather than released under acidic conditions such as the human stomach. Therefore, the combination preparation of the present invention needs to be designed so that clopidogrel, the active ingredient in the outer layer, is released in an immediate release form in the acidic conditions of the stomach, and ilaprazole, the active ingredient in the inner core tablet, is released over time in an environment of pH 5.5 or higher in the small intestine. .

The inner core tablet of the combination preparation presented in the present invention contains ilaprazole as an active ingredient, and the inner core tablet includes a coating for adhesion. Due to the nature of the press-coated tablet combination preparation, an inner core tablet is inserted inside the tablet. As a result, tabletting problems such as cracking, capping, and laminating frequently occur during tableting of the press-coated tablet combination preparation. Therefore, the tackifying coating implemented in the present invention can prevent tableting problems such as cracking, capping, and laminating that frequently occur when tableting press-coated tablets.

The combination preparation presented in the present invention is characterized in that the dissolution rate of clopidogrel in a dissolution solution of about pH 2.0, which is a gastric acid environment, is more than 75%, preferably more than 85%, within 15 minutes, and the ilaprazole layer is released at pH 5.5 or more over time. It is characterized by Therefore, the inventors of the present invention determined that, due to the nature of the press-coated tablet formulation, failure to secure a rapid dissolution rate of clopidogrel, the active ingredient in the outer layer, would affect the release of ilaprazole, the active ingredient in the inner-core tablet. Accordingly, a combination preparation was designed that ensures the dissolution rate of clopidogrel, the active ingredient in the outer layer, of more than 85% within 15 minutes.

The outer layer of the combination preparation presented in the present invention contains clopidogrel or a pharmaceutically acceptable salt thereof as an active ingredient, and is mixed with an additive having sufficient compressibility and fluidity and compressed into a tablet to reduce manufacturing costs, thereby completing the invention. . The outer layer is characterized by being manufactured by direct hitting. Since the powder in the outer layer has sufficient fluidity and compressibility, the inventors of the present invention determined that there would be no problem in the process even if the outer layer was manufactured by direct beating. In addition, manufacturing costs and powder loss can be minimized by manufacturing the outer layer using a direct pressing method.

The combination preparation presented in the present invention is characterized by a cored tablet, and in order to prevent tabletting problems that occur during compression of the cored tablet, the weight% of the inner core tablet is 10 to 30% by weight relative to the total weight of the cored tablet, specifically 15 to 20% by weight. It is characterized by

The press-coated tablet combination preparation presented in the present invention is selected from the group consisting of a diluent, a disintegrant, a binder, a lubricant, and a coating agent. Characterized in that it contains one or more additives.

The diluent in the present invention includes one or more selected from the group consisting of lactose, microcrystalline cellulose, crystalline cellulose, mannitol, pregelatinized starch, corn starch, and calcium hydrogen phosphate.

The disintegrant in the present invention includes at least one selected from the group consisting of sodium starch glycolate, sodium croscarmellose, microcrystalline cellulose, crospovidone, low-substituted hydroxypropyl cellulose, and calcium carboxymethyl cellulose.

The binder in the present invention includes at least one selected from the group consisting of polyvinylpyrrolidone, polyethylene glycol, hydroxypropylcellulose, hypromellose, microcrystalline cellulose, and methylcellulose.

The diluent in the present invention is a press-coated tablet combination preparation characterized in that it is contained in an amount of 30 to 70% by weight based on the total weight of the press-coated tablet combination preparation.

The disintegrant in the present invention is a press-coated tablet combination preparation characterized in that it is contained in an amount of 2 to 10% by weight based on the total weight of the press-coated tablet combination preparation.

The binder in the present invention is a press-coated tablet combination preparation characterized in that it is contained in an amount of 1 to 10% by weight based on the total weight of the press-coated tablet combination preparation.

The tackifying coating agent for the inner core tablet in the present invention includes polyvinylpyrrolidone, talc, polyethylene glycol, and polysorbate.

The press-coated tablet combination preparation presented in the present invention is characterized by oral administration once a day. PPI drugs other than ilaprazole can inhibit the efficacy of clopidogrel by inhibiting CYP2C19, making it difficult to co-administer the two drugs at the same time. Due to these limitations, it is recommended that clopidogrel and PPI drugs be administered with a time difference of 12 hours or more in order to prevent the drug efficacy of clopidogrel from being inhibited. Therefore, there is a problem in that the medication compliance of patients taking the drugs is greatly reduced. However, unlike other PPI drugs, ilaprazole is mostly metabolized non-enzymatically, is partially metabolized by CYP3A4, and does not inhibit CYP2C19. Therefore, ilaprazole can prevent and treat gastrointestinal disorders caused by taking clopidogrel without inhibiting the efficacy of clopidogrel. Accordingly, an inner core tablet containing ilaprazole as an active ingredient presented in the present invention; The cored tablet combination preparation consisting of an outer layer containing clopidogrel or a pharmaceutically acceptable salt thereof as an active ingredient is a preparation administered orally once a day and can greatly improve patient compliance.

The present invention relates to a press-coated tablet combination preparation containing clopidogrel or a pharmaceutically acceptable salt thereof and ilaprazole as active ingredients.

The combination preparation developed according to the present invention prevents the release of ilaprazole, a proton pump inhibitor, in the gastric acid environment and induces the release of ilaprazole in the small intestine environment over time, thereby preventing gastrointestinal disorders that occur when clopidogrel is administered alone without inhibiting the drug efficacy of clopidogrel. It can be prevented and treated.

1 shows an inner core tablet containing ilaprazole as an active ingredient; This is a schematic diagram of a press-coated tablet combination preparation consisting of an outer layer containing clopidogrel or a pharmaceutically acceptable salt thereof as an active ingredient.

Figure 2 is a graph showing the dissolution rate (%) of ilaprazole for Preparation Examples 1 to 4 and Comparative Drug 2 (Noltec Tablet).

Figure 3 is a graph showing the dissolution rate (%) of clopidogrel for Examples 1 and 2 and Comparative Drug 1 (Plavix tablets).

Hereinafter, the present invention will be described in detail through preparation examples and examples. However, the following preparation examples and examples are merely illustrative of the present invention, and the present invention is not limited by the following preparation examples and examples.

[Production Examples 1 to 4]

Ilaprazole inner core tablets were prepared according to the ingredients and contents listed in Table 1 below.

After mixing microcrystalline cellulose, pregelatinized starch, and sodium starch glycolate, the binder povidone was dissolved using ethanol and purified water to create a binder solution, and the kneading and granulation processes were performed. After drying at a temperature of 70°C, it was sized and compressed into tablets by mixing ilaprazole, magnesium hydroxide, microcrystalline cellulose, pregelatinized starch, light anhydrous silicic acid, magnesium stearate, and talc. The obtained tablets were made into inner core tablets by protective coating with Opadry 03K19229 clear, enteric coating with Acrylize 93F19255 clear, and adhesive coating using povidone, polyethylene glycol, polysorbate, and talc.

Table 1

[Test Example 1]

A dissolution test was performed on the ilaprazole inner core tablets prepared in Preparation Examples 1 to 4 according to Method 2 of the General Test Method of the Korean Pharmacopoeia. First, a dissolution test was performed in a pH 1.2 solution for 2 hours, tablets were obtained, and a dissolution test was performed at 50 rpm in 900 mL of pH 6.8 phosphate buffer containing 1% polysorbate. The results are shown in Figure 1.

[Examples 1 to 4 and Comparative Examples 1 to 2]

A clopidogrel-ilaprazole press-coated tablet combination press-coated tablet formulation was prepared according to the ingredients and contents shown in Table 2 below. Clopidogrel sulfate, lactose, microcrystalline cellulose, polyethylene glycol, hydroxypropyl cellulose, and low-substituted hydroxypropyl cellulose were mixed, and then silicon dioxide and sodium stearyl fumarate were added and mixed further. Inner core tablets were inserted into the obtained mixture and compressed into tablets to obtain core tablets, which were then coated with Opadry 03B44038 pink to prepare core tablets.

Table 2

[Comparative Example 3]

After placing spherical white sugar in a fluidized bed coater, 10 g of ilaprazole, 10 g of magnesium hydroxide, 0.5 g of hypromellose, an appropriate amount of talc, and polysorbate 80 were added to a 60% acetone solvent, and the stirred suspension was made into spheres using a fluidized bed coater. The drug was coated on white sugar. 4.356 g of Opadry 03K19229 was dissolved in 80% ethanol and then fluid-bed coated on the drug-coated spherical white sugar. Additionally, 16 g of Acrylyse 93F19255 was suspended in purified water and enteric coating was applied to the obtained spherical white sugar using a fluidized bed coater.

39.6 g of enteric-coated spherical white sugar and 100.17 g of the clopidogrel layer mixture of Example 2 were mixed and compressed into tablets using a rotary tablet press.

[Comparative Example 4]

The ilaprazole layer mixture of Preparation Example 3 and the clopidogrel layer mixture of Example 2 were tableted using a double-layer tablet rotary tablet press to obtain a double-layer tablet. Opadry 03K19229 Clear was added to 70% ethanol and dispersed to prepare a first coating solution. The obtained double-layer tablet was placed in a tablet coating machine and the first coating solution was sprayed to perform the first protective coating. Acrylize 93F19255 Clear was added to purified water and dispersed to prepare a secondary coating solution. The tablets on which the first coating was completed were placed in a tablet coating machine and enteric coating was performed by spraying the second coating solution. After coating, it was dried to obtain the final enteric-coated double-layer tablet.

[Comparative Example 5]

The ilaprazole layer mixture of Preparation Example 3 and the clopidogrel layer mixture of Example 2 were mixed and compressed into tablets using a rotary tablet press to obtain mattress tablets. Opadry 03K19229 Clear was added to 70% ethanol and dispersed to prepare a first coating solution. The obtained tablets were placed in a tablet coating machine and the first coating solution was sprayed to perform the first protective coating. Acrylize 93F19255 Clear was added to purified water and dispersed to prepare a secondary coating solution. The tablets on which the first coating was completed were placed in a tablet coating machine and enteric coating was performed by spraying the second coating solution. After coating, it was dried to obtain the final enteric-coated mattress tablet.

First, the press-coated tablet composite preparations prepared in Examples 1 to 4 and the preparations in Comparative Examples 1 to 5 were checked for occurrence of tabletting failures (cracks, capping), and the results are shown in Table 3 below.

Table 3

As a result of checking whether tableting failure occurred, it was confirmed that tabletting failure (cracks, capping, etc.) occurred in Comparative Example 1, in which no adhesive coating was applied to the inner core tablet, and Comparative Example 2, in which a small amount of the binder hydroxypropyl cellulose was contained in the outer layer. . Therefore, in order to reduce tableting difficulties, it is desirable to apply an adhesive coating to the inner core tablet and that the weight of the binder hydroxypropyl cellulose in the outer layer be more than 3% of the total weight of the core tablet.

[Test Example 2]

A dissolution test was performed on clopidogrel contained in the outer layer of the press-coated tablet combination preparation prepared in Examples 1 and 2 according to Method 2 of the General Test Method of the Korean Pharmacopoeia. A dissolution test was performed at 50 rpm in 1000 mL of pH 2.0 solution, and the results are shown in Figure 2.

[Test Example 3]

A stability test was performed on the tablets obtained in Example 2 and Comparative Examples 3 to 5 under accelerated conditions (40 ± 2°C, 75RH ± 5%). The contents of clopidogrel and ilaprazole and the contents of total related substances were measured, and the results are shown in Table 4.

Table 4

From the test results in Table 4, the press-coated tablet combination preparation of Example 2 obtained in the present invention showed higher stability under accelerated stability conditions than the preparations in the form of bead tablets, double-layer tablets, and mattress tablets of Comparative Examples 3 to 5. Specifically, the tablet of Comparative Example 3 had inadequate total related substances of clopidogrel. It is assumed that when ilaprazole enteric-coated spherical white sugar was compressed with a mixture of the clopidogrel layer, the ilaprazole component was exposed to the clopidogrel layer due to cracks in the spherical white sugar due to the tableting pressure. When the tablets of Comparative Examples 4 and 5 were stored for 6 months under accelerated stability conditions, it was confirmed that the total related substances and contents of clopidogrel and ilaprazole were inadequate. This means that if clopidogrel and ilaprazole are not completely separated, as in the press-coated tablet form of Example 2, the stability of the two components is greatly reduced.

Claims

Inner core tablet containing ilaprazole as an active ingredient; and

An outer layer containing clopidogrel or a pharmaceutically acceptable salt thereof as an active ingredient;

A press-coated tablet combination preparation containing a.
The press-coated tablet combination preparation according to claim 1, wherein the content of clopidogrel or a pharmaceutically acceptable salt thereof is 75 to 300 mg.
The press-coated tablet combination preparation according to claim 1, wherein the content of ilaprazole is 10 mg to 20 mg.
The cored tablet combination preparation according to claim 1, wherein the content of ilaprazole is 5 to 20% by weight of the mass of the inner core tablet.
The press-coated tablet combination preparation according to claim 1, wherein the inner core tablet is an enteric-coated tablet.
The cored tablet combination preparation according to claim 1, wherein the inner core tablet includes a coating for adhesion.
The press-coated tablet combination preparation according to claim 1, wherein the press-coated tablet has a dissolution rate of clopidogrel of 75% or more within 15 minutes in a pH 2.0 dissolution solution.
The press-coated tablet combination preparation according to claim 1, wherein the outer layer is manufactured by direct pressing.
The press-coated tablet combination preparation according to any one of claims 1 and 3-5, wherein the inner core tablet is 10 to 30% by weight based on the total weight of the cored tablet.
The press-coated tablet combination preparation according to claim 1, wherein the press-coated tablet combination preparation contains at least one additive selected from the group consisting of a diluent, a disintegrant, a binder, a lubricant, and a coating agent.
The press-coated tablet combination preparation according to claim 10, wherein the diluent is at least one selected from the group consisting of lactose, microcrystalline cellulose, crystalline cellulose, mannitol, pregelatinized starch, corn starch, and calcium hydrogen phosphate.
The method of claim 10, wherein the disintegrant is at least one selected from the group consisting of sodium starch glycolate, sodium croscarmellose, microcrystalline cellulose, crospovidone, low-substituted hydroxypropyl cellulose, and calcium carboxymethyl cellulose. Nuclear tablet complex preparation.
The press-coated tablet combination preparation according to claim 10, wherein the binder is at least one selected from the group consisting of polyvinylpyrrolidone, polyethylene glycol, hydroxypropylcellulose, hypromellose, microcrystalline cellulose, and methylcellulose.
The press-coated tablet combination preparation according to claim 10 or 11, wherein the diluent is contained in an amount of 30 to 70% by weight based on the total weight of the press-coated tablet combination preparation.
The press-coated tablet combination preparation according to claim 10 or 12, wherein the disintegrant is contained in an amount of 2 to 10% by weight based on the total weight of the press-coated tablet combination preparation.
The press-coated tablet combination preparation according to claim 10 or 13, wherein the binder is contained in an amount of 1 to 10% by weight based on the total weight of the press-coated tablet combination preparation.
The cored tablet combination preparation according to claim 1 or 5, wherein the inner core tablet contains at least one tackifying coating agent selected from the group consisting of polyvinylpyrrolidone, talc, polyethylene glycol, and polysorbate.
The press-coated tablet combination preparation according to claim 1, wherein the press-coated tablet combination preparation is administered orally once a day.