KR20130103384A - Pharmaceutical composition comprising clopidogrel and aspirin and process for preparing the same - Google Patents

Abstract

PURPOSE: A pharmaceutical composition containing clopidogrel and aspirin is provided to minimize a change of the content of active ingredients and the generation of related compounds, thereby having superior stability. CONSTITUTION: A pharmaceutical composition contains: aspirin-containing particles having a copolymer containing methacrylic acid and ethyl acrylate mixed in a weight ratio of 1:1 or a coating layer containing hydroxypropyl cellulose phthalate on aspirin or a salt thereof; and clopidogrel-containing particles having a coating layer containing hydroxypropyl cellulose or hydroxypropyl methylcellulose on clopidogrel or a salt thereof. A method for manufacturing the pharmaceutical composition comprises the steps of: preparing the aspirin-containing particles; preparing the clopidogrel-containing particles; and forming a capsule, a tablet, or a granule using the aspirin-containing particles and clopidogrel-containing particles and selectively using a pharmaceutically acceptable additive.

Description

Pharmaceutical composition comprising clopidogrel and aspirin and process for preparing the same}

The present invention relates to a pharmaceutical composition comprising clopidogrel and aspirin and a method for preparing the same, and more particularly, to a pharmaceutical composition having excellent stability and formulated through separate particle coating so that the clopidogrel and aspirin do not contact each other. It is about.

Clopidogrel has the chemical name Methyl (+)-(S) -α- (o-chlorophenyl) -6,7-dihydrothieno [3,2-c] pyridine-5 (4H) -acetate (the preferred optical isomer). Has platelet inhibitory activity to prevent ischemic events caused by vascular diseases such as atherosclerosis and heart failure. Clopidogrel has an antithrombotic effect by inhibiting platelet aggregation, which is useful for the prevention and treatment of various vascular diseases such as atherosclerosis, stroke, myocardial infarction and peripheral arterial obstruction. Clopidogrel is known as a salt, hydrochloride, hydrogen sulfate, bromate, taurocholine acid salt, and is currently used in the form of clopidogrel hydrogen sulfate (or sometimes referred to as sulfate, C ₁₆ H ₁₆ ClNO ₂ S · H ₂ SO ₄ ). have.

However, clopidogrel or salts thereof are representative drugs which have very poor physical properties and are very difficult to formulate. When clopidogrel or its salt is in contact with an aqueous solution, there is a problem in that they disintegrate and gelate, causing disintegration to be delayed. In particular, clopidogrel or its salts are very hygroscopic and hydrolyzed in the presence of water, resulting in low stability. For example, Clopidogrel Hydrogen Sulfate is a decomposed product, A and C (Impurity A: (+)-(S)-(o-chlorophenyl) -6,7) when stored at 65 ° C / 75% relative humidity. -dihydrothieno [3,2-c] pyridine-5 (4H) -acetic acid, Impurity C: methyl (-)-(R) -o-chlorophenyl-6,7-dihydrothieno [3,2-c] pyridine-5 (4H) -acetate and hydrogen sulfate) significantly increased over time. In addition, salts of clopidogrel, including clopidogrel or hydrogen sulphate, exhibit interactions with commonly used pharmaceutical additives, thereby causing problems of stability deterioration. For example, an undesirable interaction exists between additives containing alkali metals (Na, etc.) and / or alkaline earth metals (Ca, Mg, etc.) and clopidogrel hydrogen sulfate (US Patent Publication No. 2003). / 0096837). In addition, clopidogrel or its salt has a high surface electrostatic force, and sticking to a punch occurs when a tablet is manufactured, and mass production is difficult. The present inventors have disclosed that clopidogrel or its salt is an agent that can improve the difficult to formulate clopidogrel or its salts, such as poor stability due to hydrolysis, interaction with additives, and sticking disorders such as sticking. Stabilized clopidogrel-containing particles obtained by coating a salt with hydroxypropyl cellulose or hydroxypropyl methyl cellulose, a preparation method thereof, and a pharmaceutical composition containing the same have been developed (Korean Patent Registration No. 10-0809903).

On the other hand, aspirin, known as acetylsalicylic acid, has been used to relieve fever and pain, but recently, through platelet aggregation inhibitory action, reduces the risk of nonfatal myocardial infarction and ischemic attack in patients with unstable angina pectoris. It is used to prevent reinfarction after infarction. WO97 / 029753 discloses that synergistic effects can be expected in the inhibition of platelet activity when clopidogrel and aspirin are used in combination. International Patent Publication No. WO09 / 104932 also includes a three-layer definition comprising a prior-release compartment comprising aspirin or a salt thereof and a delayed-release compartment comprising clopidogrel or a salt thereof and comprising a placebo layer that does not contain the active ingredient. Co-formulations in the form have been disclosed. The co-formulation is a formulation in which the release pattern of the drug is controlled so that aspirin first acts, and then clopidogrel exhibits drug efficacy.

The inventors of the present invention have developed a combination of a single dosage form containing clopidogrel and aspirin as active ingredients, and found that when clopidogrel and aspirin are contacted with each other in the formulation, the content change is severe and the production of the flexible substance is increased. To solve this problem, the inventors have prepared a variety of formulations designed to prevent clopidogrel and aspirin from contacting each other in a single formulation, to test the stability and dissolution interference of the active ingredient. The present inventors carry out clopidogrel particle coating according to the inventors' patent patent No. 10-0809903, and also aspirin particle coating using a specific polymer, and the obtained particles are mixed and formulated into a single dosage form. It has been found that not only can the dissolution rate be equal to or higher than that of a single formulation comprising each component, but also excellent stability can be achieved by minimizing the change in the content of the active ingredient and the formation of the softening material.

Accordingly, it is an object of the present invention to provide a monolithic composite formulation having excellent stability in which clopidogrel and aspirin are formulated so as not to contact each other through separate particle coatings.

Moreover, an object of this invention is to provide the manufacturing method of the said composite agent.

According to one aspect of the invention, (a) aspirin-containing particles having a coating layer comprising hydroxypropyl cellulose phthalate or a 1: 1 weight ratio of methacrylic acid and ethyl acrylate on aspirin or a salt thereof; And (b) clopidogrel-containing particles having a coating layer comprising hydroxypropyl cellulose or hydroxypropyl methylcellulose on clopidogrel or a salt thereof.

In the pharmaceutical composition of the present invention, the content of the copolymer or hydroxypropyl cellulose phthalate in a 1: 1 weight ratio of methacrylic acid and ethyl acrylate may be in the range of 10 to 40 parts by weight based on 100 parts by weight of aspirin or a salt thereof. have. In addition, the content of the hydroxypropyl cellulose or hydroxypropyl methyl cellulose may range from 5 to 40 parts by weight based on 100 parts by weight of clopidogrel or salts thereof.

In the pharmaceutical composition of the present invention, the aspirin-containing particles and / or the clopidogrel-containing particles may be in powder form, granule form, pellet form, or mini tablet form. In one embodiment, the clopidogrel-containing particles may be in the form of mini tablets.

In addition, in one embodiment, the pharmaceutical compositions of the present invention may have a formulation of capsules, tablets, or granules.

According to another aspect of the present invention, (i) aspirin-containing particles are prepared by coating aspirin or a salt thereof with a coating solution comprising hydroxypropyl cellulose phthalate or a 1: 1 weight ratio of methacrylic acid and ethyl acrylate. Making; (ii) coating clopidogrel or a salt thereof with a coating solution comprising hydroxypropyl cellulose or hydroxypropyl methylcellulose to prepare clopidogrel-containing particles; And (iii) forming a capsule, tablet, or granule using the aspirin-containing particles obtained in step (i), the clopidogrel-containing particles obtained in step (ii), and optionally a pharmaceutically acceptable additive. There is provided a method of preparing a pharmaceutical composition comprising.

According to another aspect of the invention, (i) aspirin-containing particles are coated with a coating solution comprising hydroxypropyl cellulose phthalate or aspirin or a salt thereof in a 1: 1 weight ratio of methacrylic acid and ethyl acrylate. Manufacturing; (ii ') Clopidogrel- or salts thereof are coated with a coating solution comprising hydroxypropyl cellulose or hydroxypropyl methylcellulose to produce clopidogrel-containing particles, and the resulting clopidogrel-containing particles are compressed with a pharmaceutically acceptable additive. Obtaining a clopidogrel-containing tablet; And (iii ') filling the capsule with the aspirin-containing particles obtained in step (i) and the clopidogrel-containing tablet obtained in step (ii').

The pharmaceutical composition according to the present invention is a complex formulation of a single dosage form designed through particle coating using a specific polymer such that clopidogrel or a salt thereof and aspirin or a salt thereof are not in contact with each other. Excellent stability can be achieved by minimizing. In particular, the pharmaceutical composition according to the present invention can significantly lower the degradation product of aspirin due to long-term preservation. In addition, the pharmaceutical composition of the present invention is designed to exhibit a dissolution rate and bioavailability equivalent to or greater than a single agent containing each component, thereby minimizing the possibility of drug release interference.

The present invention (a) aspirin-containing particles having a coating layer comprising a copolymer or hydroxypropyl cellulose phthalate of 1: 1 weight ratio of methacrylic acid and ethyl acrylate on aspirin or a salt thereof; And (b) clopidogrel-containing particles having a coating layer comprising hydroxypropyl cellulose or hydroxypropyl methylcellulose on clopidogrel or a salt thereof.

The aspirin-containing particles have a specific enteric polymer that is, aspirin or with methacrylic acid and ethyl acrylate, a salt thereof, 1 [such as, for example, Eudragit L30D55 ^TM (Eudragit L30D55 ^TM, Evonic)] copolymers of 1 by weight Or by coating with hydroxypropyl cellulose phthalate.

The aspirin may be subjected to particle coating according to the present invention using aspirin or its salt itself (i.e. the synthesized raw material itself), and also referred to as aspirin or its salt in the form of granules (hereinafter referred to as 'aspirin granules'). Particle coating according to the invention can also be carried out using aspirin or its salt (hereinafter also referred to as an aspirin pellet) in pellet form obtained by coating aspirin or a salt thereof on an inert core. . When aspirin granules or aspirin pellets are used, particle coating can be performed more efficiently because of excellent physicochemical properties such as properties and flowability. The aspirin granules can be obtained via the conventional wet or dry granulation process, and the like can be used in the form of aspirin granules is commercially available, for example, Rodin ^{2316 TM (Rhodine 2316 TM, Rhodia} ). The aspirin pellets can be obtained by coating with aspirin, using commercially available inert cores, for example, spherical sugars. Povidone or hydroxypropyl cellulose or hydroxypropyl methylcellulose may be used as the binder in the coating.

The content of the copolymer or hydroxypropyl cellulose phthalate in a 1: 1 weight ratio of methacrylic acid and ethyl acrylate is in the range of 10 to 40 parts by weight, preferably in the range of 15 to 30 parts by weight based on 100 parts by weight of aspirin or its salt. Can be. When the content of the coating agent is less than 10 parts by weight, the stability may be lowered, and when it exceeds 40 parts by weight, the dissolution rate may be lowered. The aspirin-containing particles may further include a plasticizer such as triethyl citrate, and a lubricant such as talc, in addition to the coating agent described above, which is a 1: 1 weight ratio copolymer of methacrylic acid and ethyl acrylate in the coating process. Or by coating with a coating solution containing triethyl citrate and / or talc in addition to hydroxypropyl cellulose phthalate.

The clopidogrel-containing particles may be prepared according to Korean Patent Registration No. 10-0809903, which is the prior patent of the present inventors. That is, the clopidogrel-containing particles can be obtained by coating clopidogrel or a salt thereof with hydroxypropyl cellulose or hydroxypropyl methylcellulose. The hydroxypropyl cellulose or hydroxypropyl methyl cellulose may be coated in the range of 5 to 40 parts by weight, preferably 10 to 30 parts by weight based on 100 parts by weight of clopidogrel or its salt. When the amount of the coating is less than 5 parts by weight, the barrier film effect and / or the improvement of surface properties may be insufficient, and when the amount exceeds 40 parts by weight, the dissolution rate may be reduced. The coating layer of the clopidogrel-containing particles may include a fluidizing agent, a plasticizer, etc., if necessary, and may preferably include a fluidizing agent (silicon dioxide) or a plasticizer (polyethylene glycol) having no interaction with the active ingredient. .

In the pharmaceutical composition of the present invention, the aspirin-containing particles and / or the clopidogrel-containing particles may be in powder form, granule form, pellet form, or mini tablet form. In one embodiment, the clopidogrel-containing particles may be in the form of mini tablets (eg, minitablets having a diameter of 2-6 mm).

The clopidogrel-containing particles and aspirin-containing particles may be formulated in capsule, tablet, or granule form, optionally with pharmaceutically acceptable additives. In addition, the clopidogrel-containing particles are optionally prepared in tablet form (e.g., in the form of minitablet (diameter: 2-6 mm)) together with a pharmaceutically acceptable additive, and then the resulting tablet is prepared with aspirin-containing particles. The capsules may be filled together to be formulated in capsule form.

The pharmaceutical composition according to the present invention may have the form of an oral solid preparation, and preferably it may have a formulation of a capsule, tablet, or granule. Pharmaceutical compositions of the formulation of capsules, tablets, or granules may further comprise pharmaceutically acceptable additives such as diluents, binders, glidants and the like. Examples of the diluent include microcrystalline cellulose (for example, Ceolus ^TM ), starch, pregelatinized starch, lactose, and the like. Examples of the binder include hydroxypropyl cellulose and the like. Zinc or magnesium salts, Aerosil 200 and the like.

The present invention also includes a method for preparing the pharmaceutical composition. That is, the present invention comprises the steps of: (i) coating aspirin or a salt thereof with a coating solution comprising a copolymer or hydroxypropyl cellulose phthalate in a 1: 1 weight ratio of methacrylic acid and ethyl acrylate to prepare aspirin-containing particles; (ii) coating clopidogrel or a salt thereof with a coating solution comprising hydroxypropyl cellulose or hydroxypropyl methylcellulose to prepare clopidogrel-containing particles; And (iii) forming a capsule, tablet, or granule using the aspirin-containing particles obtained in step (i), the clopidogrel-containing particles obtained in step (ii), and optionally a pharmaceutically acceptable additive. It includes a method for producing a pharmaceutical composition comprising.

Steps (i) and (ii) may be performed in reverse order or simultaneously. The coating of step (i) and step (ii) may be carried out according to the coating method commonly used in the field of formulation, for example, may be performed according to the fluidized bed coating method. The formation of the capsules, tablets, or granules of step (iii) can also be carried out according to formulation methods commonly used in the field of formulations. For example, a capsule can be prepared by filling a capsule according to a conventional method with a mixture of aspirin-containing particles obtained in step (i), clopidogrel-containing particles obtained in step (ii), and optionally a pharmaceutically acceptable additive. It can manufacture. In addition, tablets may be prepared by tableting a mixture of the aspirin-containing particles obtained in step (i), the clopidogrel-containing particles obtained in step (ii), and optionally a pharmaceutically acceptable additive, according to conventional methods, Coating (eg, film coating) can be carried out as needed. In addition, the tablet may be prepared in the form of a two-layer tablet using a conventional multi-layer tablet press. In addition, the placebo layer granules may be added to form a three-layered tablet or more multilayered tablets as needed. The obtained two-layered tablets, three-layered tablets and the like can be coated (for example, film coating) as necessary.

The present invention also provides a method for preparing aspirin-containing particles, comprising the steps of: (i) coating aspirin or a salt thereof with a coating solution comprising a copolymer or hydroxypropyl cellulose phthalate in a 1: 1 weight ratio of methacrylic acid and ethyl acrylate to prepare aspirin-containing particles; (ii ') Clopidogrel- or salts thereof are coated with a coating solution comprising hydroxypropyl cellulose or hydroxypropyl methylcellulose to produce clopidogrel-containing particles, and the resulting clopidogrel-containing particles are compressed with a pharmaceutically acceptable additive. Obtaining a clopidogrel-containing tablet; And (iii ') filling the capsule with the aspirin-containing particles obtained in step (i) and the clopidogrel-containing tablet obtained in step (ii').

Steps (i) and (ii ') may be performed in reverse order or simultaneously. The coating of steps (i) and (ii ') may be carried out according to a coating method commonly used in the field of formulations, for example, it may be carried out according to a fluidized bed coating method and the like. Also, if desired, coating (eg, film coating) may be performed on the clopidogrel-containing tablet obtained in step (ii '). Filling the capsules of step (iii ') may also be carried out according to formulation methods commonly used in the field of formulations.

Hereinafter, the present invention will be described in more detail with reference to examples. However, these examples are for illustrating the present invention, and the scope of the present invention is not limited to these examples.

Example 1 Preparation of Aspirin-Containing Particles

Aspirin-containing particles were prepared according to the ingredients and contents in Table 1 below. In Table 1, aspirin granules were used as Rhodine 2316 ^TM (Rhodine 2316 ^TM , Rhodia), and 1,111.1 g of aspirin granules used corresponded to 1,000.0 g of aspirin. Eudragit L30D55 ^™ (Eudragit L30D55 ^™ , Evonic), triethyl citrate, and talc were dissolved and dispersed in purified water to prepare a coating solution. Aspirin granules were coated with the coating liquid using a fluidized bed coater [GPCG-1 (GLATT, Germany)] and the coating conditions were as follows: injection temperature: 40-60 ° C., discharge temperature: 25-35 ° C., product temperature: 25 to 35 ° C, injection rate: 2 to 5 mL / min

Raw material Example (g) 1-1 1-2 1-3 1-4 1-5 1-6 1-7 Aspirin granules 1,111.1 1,111.1 1,111.1 1,111.1 1,111.1 1,111.1 1,111.1 Eudragit L30D55 ^TM
(As a dry matter) 185.3
(55.6) 370.3
(111.11) 555.6
(166.7) 740.7
(222.2) 925.9
(277.8) 1,481.2
(444.4) 1,851.8
(555.6) Triethyl citrate 5.6 11.1 16.7 22.2 27.8 44.4 55.6 Talc 27.8 55.6 83.3 111.1 138.9 222.2 277.8 Purified water 226 452 678 904 1,131 1,808 2,261

Example 2. Preparation of Aspirin-Containing Particles

Aspirin-containing particles were prepared according to the ingredients and contents in Table 2 below. In Table 2 aspirin granules were used Rodin ^{2316 TM (Rhodine 2316 TM, Rhodia} ), aspirin granules of 1,111.1 g Using corresponds to 1,000.0 g aspirin. Hydroxypropyl cellulose phthalate, triethyl citrate, and talc were dissolved and dispersed in a 1: 1 mixed solvent of ethanol and acetone to prepare a coating solution. Aspirin granules were coated with the coating liquid using a fluidized bed coater [GPCG-1 (GLATT, Germany)], and the coating conditions were the same as in Example 1.

Raw material Example (g) 2-1 2-2 2-3 2-4 2-5 2-6 2-7 Aspirin granules 1,111.1 1,111.1 1,111.1 1,111.1 1,111.1 1,111.1 1,111.1 Hydroxypropyl cellulose phthalate 55.6 111.1 166.7 222.2 277.8 333.3 444.4 Triethyl citrate 8.3 16.7 25.0 33.3 41.7 50.0 66.7 Talc 27.8 55.6 83.3 111.1 138.9 166.7 222.2 ethanol 740 1,480 2,220 2,960 3,700 4,440 5,920 Acetone 740 1,480 2,220 2,960 3,700 4,440 5,920

Example 3. Preparation of Aspirin-Containing Particles

(1) Preparation of Aspirin Pellets

Aspirin pellets were prepared according to the ingredients and contents in Table 3 below. Hydroxypropyl cellulose and aspirin were dissolved and dispersed in ethanol to prepare a coating solution. Aspirin pellets were prepared by coating an inert core (spherical sugar) with the coating solution using a fluid bed coater [GPCG-1 (GLATT, Germany)]. The coating conditions were as follows: injection temperature: 45-60 ° C., discharge temperature: 25-35 ° C., product temperature: 25-35 ° C., spray rate: 8 mL / min.

Raw material Example (g) 3-1 3-2 Spherical white sugar 600 300 aspirin 600 600 Hydroxypropylcellulose 30 30 ethanol 3000 3000

(2) Preparation of Aspirin-Containing Particles

Aspirin-containing particles were prepared according to the ingredients and contents of Table 4 below. Hydroxypropyl cellulose phthalate, triethyl citrate, and talc were dissolved and dispersed in a 1: 1 mixed solvent of ethanol and acetone to prepare a coating solution. Using the fluidized bed coater [GPCG-1 (GLATT, Germany)], the aspirin pellets obtained above were coated with the coating solution, and the coating conditions were the same as in Example 1.

Raw material Example (g) 3-3 3-4 3-5 3-6 Pellets of Example 3-1
(aspirin) 1230
(600) Pellets of Example 3-2
(aspirin) 930
(600) 930
(600) 930
(600) Hydroxypropyl cellulose phthalate 123.0 93.0 139.5 186 Triethyl citrate 12.3 9.3 14.0 18.6 Talc 24.6 18.6 27.9 36.2 ethanol 1285 970 1460 1945 Acetone 1285 970 1460 1945

Examples 4 and 5. Preparation of Clopidogrel-Containing Particles

Clopidogrel-containing particles were prepared in the form of granules according to the ingredients and contents of Tables 5 and 6 below. 978.75 g of clopidogrel hydrogen sulfate used in Tables 5 and 6 correspond to 750 g of clopidogrel. Hydroxypropyl methylcellulose (Pharmacoat 603 ^™ , Shinetsu) was dispersed in a 1: 1 mixed solvent of ethanol and methylene chloride to prepare a coating solution. Clopidogrel hydrogen sulfate was coated with the coating liquid using a fluidized bed coater [GPCG-1 (GLATT, Germany)] and the coating conditions were as follows: injection temperature: 60-70 ° C., discharge temperature: 35-45 ° C., product temperature : 35 ~ 45 ℃, injection speed: 5mL / min

Raw material Example (g) 4-1 4-2 4-3 4-4 4-5 4-6 4-7 4-8 Clopidogrel Hydrogen Sulfate 978.75 978.75 978.75 978.75 978.75 978.75 978.75 978.75 Hydroxypropyl methylcellulose 3cps 21.25 51.25 117.25 181.25 241.25 301.25 391.50 489.50 ethanol 121 293 670 1,036 1,379 1,721 2,237 2,796 Methylene chloride 121 293 670 1,036 1,379 1,721 2,237 2,796

Raw material Example (g) 5-1 5-2 5-3 5-4 5-5 5-6 5-7 5-8 Clopidogrel Hydrogen Sulfate 978.75 978.75 978.75 978.75 978.75 978.75 978.75 978.75 Hydroxypropyl methylcellulose 6cps 21.25 51.25 117.25 181.25 241.25 301.25 391.50 489.50 ethanol 121 293 670 1,036 1,379 1,721 2,237 2,796 Methylene chloride 121 293 670 1,036 1,379 1,721 2,237 2,796

Example 6 Preparation of Clopidogrel-Containing Minitablets

Clopidogrel-containing minitablets were prepared according to the ingredients and contents in Table 7. The content of Table 7 shows the content per mini tablet. Clopidogrel-containing particles (particles of Example 4-3), microcrystalline cellulose and L-hydroxypropyl cellulose (L-HPC) were mixed, and then the mixture of Aerosil 200 and stearyl fumarate was again mixed. After mixing, tableting was carried out to prepare a mini-tablet (diameter: 6 mm). Examples 6-2 and 6-3 were further film coated. That is, hydroxypropyl methyl cellulose, polyethylene glycol 6000, titanium oxide and iron oxide (iron oxide) was dispersed in purified water to prepare a coating solution, and then the mini tablets were coated.

Raw material Example (mg) 6-1 6-2 6-3 Clopidogrel-containing particles Example 4-3 109.6 109.6 109.6 additive Microcrystalline cellulose 52.4 52.4 52.4 L-hydroxypropyl cellulose 12.0 12.0 12.0 Aerosil 200 3.0 3.0 3.0 Sodium stearyl fumarate 3.0 3.0 3.0 Coating agent Hydroxypropyl methylcellulose 8.0 16.0 Polyethylene Glycol 6000 1.0 2.0 Titanium oxide 0.9 1.8 Iron sulfate 0.1 0.2 Total amount 180 190 200

Examples 7 and 8. Preparation of Capsules

Capsules were prepared according to the ingredients and contents of Tables 8 and 9 below. The contents of Table 8 and Table 9 represent the contents per capsule. Clopidogrel-containing particles were mixed with talc (the capsules of Example 7-7 further mixed with microcrystalline cellulose) to obtain mixture A, and aspirin-containing particles were mixed with talc to obtain mixture B. A capsule was prepared by manually filling mixture A first in a blank capsule of size and then filling mixture B.

Example (mg) 7-1 7-2 7-3 7-4 7-5 7-6 7-7 Clopidogrel-containing particles Example 4-2 102.0 Example 4-3 109.6 109.6 Example 4-4 116.0 Example 4-5 122.0 Examples 4-6 128.0 Examples 4-7 137.0 Microcrystalline cellulose 37.0 Talc 4.0 4.4 5.0 5.0 5.0 5.0 4.4 Aspirin-containing particles Example 1-4 146.67 146.67 146.67 146.67 146.67 146.67 146.67 Talc 4.33 4.33 4.33 4.33 4.33 4.33 4.33 Total amount 257 265 272 278 284 293 302

Example (mg) 8-1 8-2 8-3 8-4 8-5 8-6 8-7 8-8 Clopidogrel-containing particles Example 4-3 109.6 109.6 109.6 109.6 109.6 109.6 109.6 109.6 Talc 4.4 4.4 4.4 4.4 4.4 4.4 4.4 4.4 Aspirin-containing particles Examples 1-2 128.89 Example 1-3 137.78 Example 1-4 146.67 Examples 1-5 155.56 Examples 1-6 182.21 Example 2-3 138.61 Examples 2-4 147.77 Example 2-5 156.95 Talc 4.11 4.22 4.33 4.44 5.79 4.39 4.23 5.05 Total amount 247 256 265 274 302 257 266 276

Example 9 Preparation of Capsules

A capsule was prepared according to the ingredients and contents in Table 10 below. The content in Table 10 represents the content per capsule. The capsules were prepared by manually filling clopidogrel-containing tablets first, followed by aspirin-containing particles.

Raw material Example (mg) 9-1 9-2 9-3 9-4 Clopidogrel-Containing Tablets Example 6-1 180.0 180.0 Example 6-3 200.0 200.0 Aspirin-containing particles Example 3-3 231.65 231.65 Example 3-4 175.15 175.15 Total amount 411.65 431.65 355.15 375.15

Example 10 Preparation of Tablets

Tablets were prepared according to the ingredients and contents in Table 11 below. Table 11 shows the content per tablet. Clopidogrel-containing particles, aspirin-containing particles, microcrystalline cellulose, starch 1500, and L-hydroxypropyl cellulose (L-HPC) were mixed, and then a mixture of Aerosil 200 and stearic acid was mixed again. After that, it was compressed into tablets to prepare a tablet.

Example (mg) 10-1 10-2 10-3 10-4 Clopidogrel-containing particles Example 4-3 109.6 109.6 Example 5-3 109.6 109.6 Aspirin-containing particles Example 1-4 146.67 146.67 Examples 2-4 147.77 147.77 additive Microcrystalline cellulose 114.73 114.73 113.63 113.63 Starch 1500 77 77 77 77 L-HPC 20 20 20 20 Aerosil 200 6 6 6 6 Stearic acid 6 6 6 6 Total amount 480 480 480 480

Comparative Examples 1-6. Preparation of capsules

According to the ingredients and contents of Table 12 below, capsules were prepared in the same manner as in Examples 7 and 8. 111.11 mg of aspirin granules used in Comparative Example 1 correspond to 100 mg of aspirin and 97.875 mg of clopidogrel hydrogen sulfate corresponds to 75 mg of clopidogrel.

Comparative Example (mg) One 2 3 4 5 6 Clopidogrel-containing particles Clopidogrel Hydrogen Sulfate 97.875 Example 4-1 100.0 101.0 Example 4-3 109.6 109.6 Examples 4-8 146.8 Microcrystalline cellulose 20.125 Talc 5.0 4.0 6.2 4.4 4.4 4.0 Aspirin-containing particles Aspirin granules 111.11 Example 1-1 120.01 120.01 Example 1-4 146.67 146.67 Examples 1-7 200.01 Talc 3.89 4.33 4.33 3.99 5.99 3.99 Total amount 238 255 304 238 320 229

Test Example 1. In vitro dissolution rate evaluation (clopidogrel)

Example 7-1 to 7-7, 9-1, 9-2, 10-1, 10-2, and the dissolution rate was carried out by performing a dissolution test in a pH 2.0 buffer for 30 minutes to the capsules prepared in Comparative Example 3 %) Was measured, and the results are shown in Tables 13 and 14 below.

Example (%) Comparative example 7-1 7-2 7-3 7-4 7-5 7-6 7-7 3 pH2.0 100.2 100.6 95.7 88.3 85.3 81.7 100.1 61.3

Example (%) 9-1 9-2 10-1 10-2 pH2.0 97.6 92.1 99.9 98.4

From the results in Table 13, the capsules obtained from clopidogrel-containing particles having hydroxypropyl methylcellulose coated at 40 parts by weight or less with respect to 100 parts by weight of clopidogrel hydrogen sulfate showed a good dissolution rate of 80% or higher, which is the standard of the USP. It can be seen that. In contrast, the capsule obtained from clopidogrel-containing particles having hydroxypropyl methylcellulose coated in excess of 40 parts by weight with respect to 100 parts by weight of clopidogrel hydrogen sulfate, that is, the capsule of Comparative Example 3, significantly inhibited the drug release of clopidogrel. In addition, from the results in Table 14, it can be seen that the tablets obtained by tableting the capsules and clopidogrel-containing particles filled with mini-tablets obtained from clopidogrel-containing particles also exhibited a good dissolution rate of 80% or more, which is a standard of the USP. .

Test Example 2 Evaluation of in vitro dissolution rate (aspirin)

Dissolution rate (%) by performing dissolution test on the capsules prepared in Examples 8-1 to 8-8, 9-1, 9-3, 10-1, 10-3, and Comparative Examples 1, 4 and 5 Was measured. Specifically, each capsule was subjected to an elution test for 2 hours in a pH 1.0 buffer, followed by a dissolution test for 90 minutes in a buffer adjusted to pH 6.8 by adding 0.2 M sodium triphosphate solution to the remaining formulation. The results are shown in Tables 15 and 16 below.

Example Comparative example 8-1 8-2 8-3 8-4 8-5 8-6 8-7 8-8 One 4 5 pH1.0 9.4 5.9 4.0 3.2 2.5 5.4 4.6 3.9 96.5 18.9 1.2 pH6.8 92.7 102.2 100.3 89.7 82.8 101.2 99.7 93.8 98.0 102.3 74.5

Example 9-1 9-3 10-1 10-3 pH1.0 2.0 1.8 7.8 8.5 pH6.8 95.8 98.0 95.2 96.5

From the results shown in Table 15, it can be seen that the capsules prepared according to the present invention exhibit a low aspirin dissolution rate of less than 10% in the pH 1.0 buffer and are mostly eluted in the pH 6.8 buffer. In contrast, the capsule of Comparative Example 1 prepared from non-coated aspirin was prepared from aspirin-containing particles in which most of the aspirin was eluted in pH 1.0 buffer and the coating was coated at less than 10 parts by weight with respect to 100 parts by weight of aspirin granules. The prepared capsule of Comparative Example 4 did not exhibit resistance under gastric juice conditions and was eluted in excess of 10%. In addition, the capsule of Comparative Example 5 prepared from aspirin-containing particles coated with more than 40 parts by weight with respect to 100 parts by weight of aspirin had little drug dissolution under gastric juice conditions. The dissolution rate was lower than the standard of 80%. In addition, from the results in Table 16, tablets obtained by tableting aspirin-containing particles and aspirin-containing particles obtained using aspirin pellets also exhibit low aspirin dissolution rates within 10% in pH 1.0 buffer, and pH 6.8 buffer. Among them, it can be seen that the dissolution rate of more than 80%, which is the standard of the USP.

Test Example 3. Stability Test

The capsules prepared in Examples 7-2, 7-6, 8-3, 8-7 and Comparative Examples 1, 2, 4, and 6 were subjected to accelerated tests at 40 ° C. and 75% RH for 1 month. . Accelerated test results are shown in Table 17 (content,%) and Table 18 (flexible material,%). In Table 18, analog A and analog C are analogs derived from clopidogrel, and salicylic acid represents a degradation product of aspirin.

Active ingredient content change (1 month accelerated test) Storage condition ingredient Example Comparative example 7-2 7-6 8-3 8-7 One 2 4 6 0 months Clopidogrel 100.7 100.9 101.0 100.3 99.8 100.1 100.2 101.2 aspirin 100.1 100.4 99.9 99.5 100.2 100.7 100.8 100.8 1 month acceleration Clopidogrel 99.9 99.4 100.2 100.7 92.7 96.5 99.1 94.2 aspirin 101.4 102.0 100.6 99.9 83.2 99.6 94.2 89.3

Change of Lead Content (1 month accelerated test) Storage condition ingredient Example Comparative example 7-2 7-6 8-3 8-7 One 2 4 6 0 months Leading substance A 0.12 0.13 0.13 0.12 0.13 0.13 0.12 0.12 Leading substance C 0.09 0.08 0.09 0.10 0.10 0.10 0.09 0.09 Salicylic acid 0.10 0.11 0.10 0.10 0.11 0.11 0.12 0.10 Total flexible material 0.31 0.32 0.32 0.31 0.33 0.34 0.33 0.34 1 month acceleration Leading substance A 0.15 0.14 0.14 0.14 1.14 0.33 0.26 0.56 Leading substance C 0.10 0.09 0.09 0.09 0.38 0.21 0.19 0.23 Salicylic acid 0.39 0.38 0.40 0.39 7.53 1.88 2.99 5.10 Total flexible material 0.61 0.64 0.62 0.63 9.14 2.33 3.54 5.87

As can be seen from the results of Table 17 and Table 18, the capsule of Comparative Example 1 prepared without the pharmaceutical treatment significantly reduced the stability of both drugs due to the interaction between drugs. In addition, the capsules of Comparative Example 6, in which both components were coated with a relatively low content of the coating agent, showed a result of poor stability of both drugs. The capsule of Comparative Example 2 prepared from clopidogrel-containing particles coated at less than 5 parts by weight with respect to 100 parts by weight of clopidogrel hydrogen sulfate increased the content of clopidogrel related related substances and slightly increased salicylic acid. In addition, the capsule of Comparative Example 4 prepared from less than 5 parts by weight of the aspirin-containing particles with respect to 100 parts by weight of aspirin granules significantly increased the content of salicylic acid. On the contrary, the capsules prepared according to the present invention, that is, the capsules of Examples 7-2, 7-6, 8-3, and 8-7 showed little change in the content of the active ingredient, and the formation of the flexible substance was also remarkable. Low, showing excellent stability.

Claims (12)

(a) aspirin-containing particles having a coating layer comprising hydroxypropyl cellulose phthalate or a 1: 1 weight ratio of methacrylic acid and ethyl acrylate on aspirin or a salt thereof; And (b) clopidogrel-containing particles having a coating layer comprising hydroxypropyl cellulose or hydroxypropyl methylcellulose on clopidogrel or a salt thereof. The pharmaceutical composition of claim 1, wherein the aspirin or salt thereof is in granule form or pellet form. The content of the copolymer or hydroxypropyl cellulose phthalate in a 1: 1 weight ratio of methacrylic acid and ethyl acrylate is in the range of 10 to 40 parts by weight based on 100 parts by weight of aspirin or salts thereof. Pharmaceutical composition. The pharmaceutical composition according to claim 1, wherein the content of hydroxypropyl cellulose or hydroxypropyl methylcellulose is in the range of 5 to 40 parts by weight based on 100 parts by weight of clopidogrel or its salt. The pharmaceutical composition of claim 1, wherein the aspirin-containing particles or the clopidogrel-containing particles are in powder form, granule form, pellet form, or mini tablet form. The pharmaceutical composition of claim 1, wherein the clopidogrel-containing particles are in the form of mini tablets. The pharmaceutical composition according to any one of claims 1 to 6, having a formulation of capsules, tablets, or granules. (i) coating aspirin or a salt thereof with a coating solution comprising hydroxypropyl cellulose phthalate or a 1: 1 weight ratio of methacrylic acid and ethyl acrylate to prepare aspirin-containing particles;
(ii) coating clopidogrel or a salt thereof with a coating solution comprising hydroxypropyl cellulose or hydroxypropyl methylcellulose to prepare clopidogrel-containing particles; And
(iii) forming a capsule, tablet, or granule using the aspirin-containing particles obtained in step (i), the clopidogrel-containing particles obtained in step (ii), and optionally a pharmaceutically acceptable additive.
Method for producing a pharmaceutical composition comprising a. (i) coating aspirin or a salt thereof with a coating solution comprising hydroxypropyl cellulose phthalate or a 1: 1 weight ratio of methacrylic acid and ethyl acrylate to prepare aspirin-containing particles;
(ii ') Clopidogrel- or salts thereof are coated with a coating solution comprising hydroxypropyl cellulose or hydroxypropyl methylcellulose to produce clopidogrel-containing particles, and the resulting clopidogrel-containing particles are compressed with a pharmaceutically acceptable additive. Obtaining a clopidogrel-containing tablet; And
(iii ') filling the capsule with the aspirin-containing particles obtained in step (i), the clopidogrel-containing tablet obtained in step (ii')
Method for producing a capsule comprising a. The method according to claim 8 or 9, wherein the aspirin or a salt thereof is in a granular form or a pellet form. The content of the copolymer or hydroxypropyl cellulose phthalate in a 1: 1 weight ratio of methacrylic acid and ethyl acrylate is in the range of 10 to 40 parts by weight based on 100 parts by weight of aspirin or a salt thereof. Production method characterized in that. The method according to claim 8 or 9, wherein the content of hydroxypropyl cellulose or hydroxypropyl methyl cellulose is in the range of 5 to 40 parts by weight based on 100 parts by weight of clopidogrel or its salt.