WO2017160101A1 - Composite preparation containing clopidogrel and aspirin - Google Patents

Abstract

The present invention relates to a composite preparation containing clopidogrel and aspirin and to a method for preparing the same, wherein the composite preparation has stability maintained even during storage and distribution and shows a fast clopidogrel tablet disintegration rate.

Description

Combination formulations including clopidogrel and aspirin

The present invention relates to a combination formulation comprising clopidogrel and aspirin and a method for producing the same.

Clopidogrel in the present invention is an effective platelet aggregation inhibitor in the treatment of peripheral or coronary artery diseases such as stroke, thrombosis, embolism, myocardial infarction, the chemical name is methyl (+)-(S) -α- (2-chlorophenyl)- 6,7-dihydrothieno [3,2-c] pyridine-5 (4H) -acetate.

Clopidogrel directly inhibits ADP binding to adenosinediphosphate (hereinafter referred to as 'ADP') receptors, which are known to play an important role in thrombus formation, followed directly by ADP-mediated activation of the glycoprotein GPIIb / IIa complex. Thereby specifically inhibiting ADP-induced platelet aggregation. Clopidogrel also inhibits platelet aggregation caused by agonists other than ADP by blocking amplification of platelet activation by released ADP.

The pharmacological action of clopidogrel is caused by an active metabolite formed by metabolism in the liver after oral administration of clopidogrel. This active metabolite selectively and irreversibly modifies the ADP receptor on platelets, thereby preventing ADP from binding to the ADP receptor. Therefore, the effect of clopidogrel is highly dependent on the enzyme that metabolizes clopidogrel in the liver.

The chemical name for clopidogrel bisulfate (or clopidogrel hydrosulfate), a representative pharmaceutical ingredient of clopidogrel, is methyl (+)-(S) -α- (2-chlorophenyl) -6,7-dihydrothieno [3,2- c] pyridine-5 (4H) -acetate sulfate (1: 1), molecular weight 419.1, and the empirical formula is C ₁₆ H ₁₆ ClNO ₂ S.H ₂ SO ₄ .

Clopidogrel bisulfate is used for thrombotic events such as acute myocardial infarction (MI), acute stroke, or established arterial disease. It has been prescribed for reduction and has been shown to reduce the rate of combined end points of new ischemic stroke, new MI, and other vascular deaths. In patients with acute coronary syndrome, clopidogrel bisulfate has been shown to reduce the rate of multiple endpoints of cardiovascular death, MI, stroke, or refractory ischemia.

Aspirin (common name: acetylsalicylic acid), also known as one of the most effective drugs for preventing thrombus formation, is often used as an analgesic (for mild pain and pain), antipyretic (for fever), and anti-inflammatory agents. Aspirin also has an anticoagulant (blood thinning) effect and is used to prevent heart attacks at low, long-term doses.

Aspirin is generally administered between 30 mg and 1200 mg per day in one or several doses for the prevention of transient ischemic attacks and for the prevention of arterial thrombosis. Aspirin can be used to reduce the possibility of dangerous blood clots, thereby reducing the likelihood of a heart attack, stroke, or other problems that can occur when blood vessels are blocked by blood clots.

Aspirin irreversibly blocks the production of thromboxane A2 in platelets even at low doses for prolonged periods of time, which has the effect of inhibiting platelet aggregation, and this thinning of blood is useful for reducing the incidence of heart attacks.

Aspirin is also known to activate enzymes that convert clopidogrel into an active metabolite in the liver. Therefore, many studies have been made on the formulation of clopidogrel and aspirin, but there is a problem that eutectic phenomenon occurs when the two drugs are in direct contact. First of all, aspirin is a substance that absorbs a small amount of gastrointestinal absorption, but aspirin itself has a property that hurts the stomach, so the amount of use is considerable. This risk is exacerbated in formulations in which aspirin is first eluted for metabolism of clopidogrel.

Clopidogrel or a salt thereof is also a representative drug which is very difficult to formulate due to its very poor physical properties. They are sensitive to moisture and have a problem in that disintegration is delayed, such as agglomeration and gelation when they come in contact with an aqueous solution. In particular, clopidogrel or its salt is very hygroscopic and hydrolyzed in the presence of water, resulting in low stability.

Accordingly, the present inventors have devised the following inventions to solve the problem of deterioration of stability during storage and distribution of the preparation containing clopidogrel and to solve the problem of reduction of disintegration rate that occurs when clopidogrel is a tablet.

The present invention seeks to provide a combination formulation comprising clopidogrel tablets and aspirin-containing particles with increased stability during storage and distribution, wherein the aspirin-containing particles may be in the form of granules or pellets.

In another aspect, the present invention is to provide a composite formulation with an increased disintegration rate of clopidogrel tablets present in the composite formulation.

Furthermore, when the present invention is to provide a combination of clopidogrel and aspirin in the form of a capsule, including clopidogrel in the form of a tablet, the size of the tablet should be adjusted to be included in the capsule, in this case, the content ratio of clopidogrel in the tablet. Increasingly, sticking and capping may occur when the tablet is stuck. In order to prevent such a problem, the present invention also provides a clopidogrel tablet prepared by first mixing the colloidal silicon oxide with the main component and a complex preparation comprising the same.

As one aspect for achieving the above object, the present invention is a clopidogrel tablet comprising clopidogrel, isomers thereof or a pharmaceutically acceptable salt thereof; And an aspirin core comprising aspirin, an isomer thereof or a pharmaceutically acceptable salt thereof, and aspirin particles comprising an enteric coating layer surrounding the core.

In the present specification, the part disclosed with respect to "clopidogrel" may be interpreted to include all of "clopidogrel, its isomer, or a pharmaceutically acceptable salt thereof".

In another embodiment, the present invention comprises a step of preparing a clopidogrel tablet by first mixing clopidogrel, an isomer thereof, or a pharmaceutically acceptable salt thereof, and colloidal silicon oxide, and then adding a disintegrant. It provides a method of manufacturing.

The present invention solves the problem of inferior stability of the co-formulation during storage and distribution by making clopidogrel comprising clopidogrel, an isomer thereof or a pharmaceutically acceptable salt thereof.

The co-formulation may be a capsule comprising clopidogrel tablets and aspirin containing particles, and in one embodiment the capsule may be a hard capsule.

When clopidogrel is encapsulated in a capsule in the form of tablets rather than granules, the disintegration of clopidogrel may be delayed. Thus, the present invention is based on the total weight of clopidogrel tablets, based on the total weight of clopidogrel tablets, 2 to 8 wt%, more specifically As it was solved by including 3 to 5% by weight. If the content of the disintegrant is less than 2% by weight based on the total weight of the clopidogrel tablet, the desired disintegration rate cannot be obtained, and if it exceeds 8% by weight, the tablet is less stable when exposed to the atmosphere. The disintegration time of the clopidogrel tablet in the co-formulation of aspirin is 12 minutes or more, but another feature is that in the co-formulation of the present invention, clopidogrel can disintegrate at a higher rate than this. In the composite formulation of the present invention, clopidogrel may be included in the form of a tablet, and thus, a problem of decreasing the disintegration rate may be exhibited as compared to the case of including clopidogrel in the form of granules. have. In addition, the co-formulation of the present invention first elutes clopidogrel in the stomach, and aspirin granules may be eluted later in the intestine. can do.

Clopidogrel tablets present in the co-formulations of the present invention may contain a disintegrant, thereby shortening the disintegration time to less, specifically 11 minutes or less, more specifically 7 minutes or less.

The disintegrant may be a starch or modified starch such as sodium starch glycolate, corn starch, potato starch or starch gelatinized starch, clay such as bentonite, montmorillonite, veegum, microcrystalline cellulose, hydroxypropyl cellulose or Celluloses such as carboxymethyl cellulose, algins such as sodium alginate or alginic acid, cross-linked celluloses such as croscarmellose sodium, gums such as guar gum and xanthan gum, and crosslinked polyvinylpyrrolidone ( crospovidone) and mixtures thereof. More specifically, the disintegrant may be polyvinylpyrrolidone or the like.

In addition, when the clopidogrel tablets are encapsulated in the capsule, the weight of the clopidogrel tablet may be 120 to 350 mg, specifically 150 to 250 mg, more specifically 180 to 240 mg, and may be prepared differently according to actual prescription standards.

When clopidogrel tablets are encapsulated in capsules, clopidogrel tablet size is limited, so the weight ratio of clopidogrel to clopidogrel tablet weight can be as high as 50% or more, so sticking, capping and sticking to the punch during tableting There is a problem in which a phenomenon of capping occurs.

In order to solve this problem, the colloidal silicon oxide may be first mixed with clopidogrel, and then clopidogrel tablets may be prepared by adding other additives such as disintegrants.

In addition, clopidogrel tablets may use excipients having a loss of drying of less than 5% by weight, more preferably 1.5% by weight or less. Here, when the weight loss of the excipient is more than 5% by weight, tableting disorders such as sticking may occur.

The excipient may be selected from the group consisting of white sugar, D-mannitol, microcrystalline cellulose, polyethylene glycol, low-substituted hydroxypropyl cellulose, colloidal silicon oxide, and combinations thereof, and the excipient may be microcrystalline cellulose (microcrystalline cellulose, MCC). In addition, in one embodiment, the excipient is MCC 112.

In one embodiment, the capsule material may be gelatin or hydroxypropyl methylcellulose (HPMC), more preferably HPMC, but not particularly limited thereto.

Hereinafter, the complex preparation in this invention is demonstrated concretely. Meanwhile, each of the descriptions and the embodiments disclosed herein may be applied to each of the other descriptions and the embodiments. That is, all combinations of the various elements disclosed herein are within the scope of the present invention. In addition, the scope of the present invention is not to be limited by the specific description described below.

Clopidogrel and aspirin included in the co-formulation of the present invention may exist in the form of a pharmaceutically acceptable salt. Salts may be useful, but are not particularly limited, acid addition salts formed with pharmaceutically acceptable free acids.

The kind of the salt is not particularly limited. However, it is preferable that the form is safe and effective for an individual such as a mammal, but is not particularly limited thereto.

The term "pharmaceutically acceptable" means a substance that can be effectively used for a desired use without causing excessive toxicity, irritation, or allergic reactions within the scope of the medical judgment.

As used herein, the term "pharmaceutically acceptable salts" includes salts derived from pharmaceutically acceptable inorganic acids, organic acids, or bases. Examples of suitable acids include hydrochloric acid, bromic acid, sulfuric acid, nitric acid, perchloric acid, fumaric acid, maleic acid, phosphoric acid, glycolic acid, lactic acid, salicylic acid, succinic acid, toluene-p-sulfonic acid, tartaric acid, acetic acid, citric acid, methanesulfonic acid, formic acid , Benzoic acid, malonic acid, naphthalene-2-sulfonic acid, benzenesulfonic acid and the like. Salts derived from suitable bases may include alkali metals such as sodium, potassium, alkaline earth metals such as magnesium, and ammonium and the like.

Acid addition salts can be prepared by conventional methods, for example by dissolving a compound in an excess of aqueous acid solution and precipitating the salt using a water miscible organic solvent such as methanol, ethanol, acetone or acetonitrile. Equivalent molar amounts of the compound and acid or alcohol (eg, glycol monomethylether) in water can be heated and the mixture can then be evaporated to dryness or the precipitated salts can be suction filtered.

Bases can also be used to make pharmaceutically acceptable metal salts. Alkali metal salts or alkaline earth metal salts can be obtained, for example, by dissolving the compound in an excess of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and then evaporating and drying the filtrate.

More specifically, the pharmaceutically acceptable salt of clopidogrel of the present invention may be selected from the group consisting of hydrogen sulfate, resinate salt, chamlate salt, besylate salt, napadisilate monohydrate salt, hydrochloride salt and mixtures thereof of clopidogrel. have.

Colloidal silicon dioxide (fumed silica) is CAS No. 7631-86-9, which serves as an excipient in the present invention, has the effect of reducing tableting disorders during tableting.

The content of the colloidal silicon oxide may be 2 to 10% by weight based on the total weight of the clopidogrel tablet. If included below the range of sticking occurs during tableting, it is difficult to commercially continuous production, if included in the above range, capping may occur during tableting and disintegration may be delayed.

The particle size of the colloidal silicon oxide may be about 7-16 nm and may have a specific surface area of 200-400 m 2 / g.

Clopidogrel tablets of the present invention may be further coated, without limitation to the coating material, and in one embodiment the coating material may be a neocoat.

The aspirin containing particles may be in powder, granule, pellet, minitablet form, and in one embodiment may be granule or pellet.

The aspirin-containing particles specifically comprise an inner core comprising an excipient, an aspirin outer core which is adjacent to the outside of the inner core and contains as an aspirin, an isomer thereof or a pharmaceutically acceptable salt thereof and a binder as a pharmacologically active ingredient, and an outer core of the outer core. It may comprise an enteric coating layer adjacent to the outside and comprising an enteric coating. The inner core and aspirin outer core correspond to the aspirin core. Specifically, the excipient of the inner core may be a spherical white sugar, and the enteric coating layer may further include a plasticizer.

The enteric coating layer surrounding the aspirin core means a layer surrounding the core to protect the aspirin core, and the enteric coating agent, which is a material of the coating layer, can be used without limitation as long as it is a material that disintegrates in a high pH serous environment. Shellac, hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, cellulose acetate phthalate, cellulose acetate, polyvinyl alcohol phthalate, methacrylic acid-methyl methacrylate copolymer, methyl acrylate-methyl methacrylate-meth It may include one or more materials selected from the group consisting of methacrylic acid copolymer, methacrylic acid-ethylacrylic acid copolymer and mixtures thereof.

Among these, methacrylic acid-methylmethacrylic acid copolymer is methacrylic such as Eudragit L 100, Eudragit L 12.5, Eudragit L 100 P of Evonik Degussa (Germany). The molar ratio of acid and methylmethacrylic acid is 1: 1, or the molar ratio of methacrylic acid and methylmethacrylic acid such as Eudragit S 100, Eudragit S 12.5 and Eudragit S 100 P is 1: 2. desirable.

In addition, the methylacrylic acid-methylmethacrylic acid-methacrylic acid copolymer has a molar ratio of methylacrylic acid, methylmethacrylic acid and methacrylic acid such as Eudragit FS 30D of Evonik Degussa (Germany) 7: 3: 1. Is preferably.

Furthermore, the methacrylic acid-ethylacrylic acid copolymer has a molar ratio of methacrylic acid and ethyl acrylic acid such as Eudragit L 30 D-55 and Eudragit L 100-55 of Evonik Degussa (Germany). It is preferable.

The enteric coating layer may be included in an embodiment 2.0 to 20% by weight, in another embodiment 5 to 15% by weight, in another embodiment 5 to 12% by weight based on the total weight of aspirin particles. If the coating layer is formed below the above range, undesired release may occur. If the coating layer is formed above the above range, the dissolution rate is decreased and the acid resistance is poor, thereby reducing the bioavailability. May occur.

In addition, the clopidogrel tablet or aspirin-containing particles may further include an additive selected from the group consisting of diluents, binders, lubricants, stabilizers, film coating agents, plasticizers and mixtures thereof.

The binder may be a silicate derivative such as hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone, copovidone, macrogol, hard anhydrous silicic acid, synthetic aluminum silicate, calcium silicate or magnesium metasilicate aluminate; Phosphates such as calcium hydrogen phosphate; Carbonates such as calcium carbonate; And it can be selected from the group consisting of a mixture thereof, more preferably may be selected from the group consisting of hypromellose, polyvinylpyrrolidone and mixtures thereof. The binder is 1% to 5% by weight, more specifically 1% to 4% by weight based on the total weight of the tablet or particle.

The diluent is calcium carbonate, calcium phosphate, cellulose, dextrin, dextrose, ethylcellulose, fructose, glyceryl palmitostearate, maltose, sucrose, starch, microcrystalline cellulose, lactose, glucose, mannitol, alginate, Alkaline earth metal salts, clay, polyethylene glycol, dicalcium phosphate and mixtures thereof.

The lubricant may be selected from the group consisting of talc, stearic acid and its salts, sodium lauryl sulfate, hydrogenated vegetable oil, sodium benzoate, sodium stearyl fumarate, glyceryl monostearate, polyethylene glycol and mixtures thereof, more preferably Preferably sodium stearyl fumarate.

The stabilizer may be selected from the group consisting of butylated hydroxy toluene (BHT), butylated hydroxy anisole (BHA), ascorbic acid, tocopherol, edetic acid (EDTA) and mixtures thereof.

The film coating agent is gelatin, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyethylene glycol, shellac, ethyl cellulose, methyl hydroxyethyl cellulose, hydroxyethyl cellulose, sodium carboxymethyl cellulose, polyvinyl alcohol, Polyvinylpyrrolidone, polymer of vinylpyrrolidone and vinyl acetate, methyl methacrylate methacrylate trimethylammonium chloride ethyl copolymer (e.g. Eudragit RS or RL, degussa), meta Ethyl methyl acrylate copolymer (e.g., Eudragit NE30D, degussa), polyvinylacetyldimethylaminoacetate, and mixtures thereof.

The plasticizer may be selected from the group consisting of glycols, esters, oils, glycerin, glycerin derivatives, and mixtures thereof, wherein glycol may be selected from the group consisting of propylene glycol, polyethylene glycol, and mixtures thereof, and esters may be selected from phthalic acid. It may be selected from the group consisting of ethyl, dibutyl phthalate, dibutyl sebacate, triethyl citrate, acetyl triethyl citrate, acetyl tributyl citrate, triacetin and mixtures thereof. The oil may be selected from the group consisting of castor oil, coconut oil, and mixtures thereof, and glycerin and glycerin derivatives may be selected from the group consisting of glycerin, monostearine glycerin and mixtures thereof.

In the co-formulation of the present invention, the clopidogrel tablet or aspirin-containing particles may further include a rapid release material to increase the release rate, and the rapid release material may be selected from a blowing agent, a buffer, and a mixture thereof.

The blowing agent may include a carbonic acid-containing inorganic material and an organic acid.

The buffer is selected from the group consisting of calcium carbonate, sodium dihydrogen phosphate, sodium dihydrogen phosphate, sodium glutamate, potassium citrate, sodium bicarbonate, sodium citrate, sodium hydroxide, calcium phosphate, calcium hydrogen phosphate, or various salts and mixtures thereof. Can be.

In one embodiment, the total amount of aspirin particles may be 10 to 1000 parts by weight, specifically 30 to 200 parts by weight, relative to 100 parts by weight of the clopidogrel tablet in the co-formulation.

In one embodiment the co-formulation may comprise 75 mg as clopidogrel and 100 mg as aspirin, or 75 mg as clopidogrel and 75 mg as aspirin.

The co-formulation of the present invention first elutes clopidogrel tablets in the stomach, and aspirin particles are eluted in the intestine. Therefore, while complementary pharmacological effects of clopidogrel and aspirin can be expressed, gastric wall damage caused by aspirin can be prevented. In addition, by blocking the direct contact between clopidogrel and aspirin can prevent the eutectic phenomenon to prevent changes in the content or dissolution properties and to improve the stability of the drug.

The preparation method of the co-formulation of the present invention comprises mixing clopidogrel, an isomer thereof, or a pharmaceutically acceptable salt thereof, and colloidal silicon oxide, and then adding an additive to prepare the clopidogrel tablet; Preparing an aspirin core comprising an aspirin, an isomer thereof or a pharmaceutically acceptable salt thereof; And it may include the step of coating the aspirin core with an enteric coating. The clopidogrel tablets and coated aspirin particles may further comprise the step of filling the capsule.

Co-formulations of the invention may include pharmaceutically effective amounts of clopidogrel tablets and aspirin containing particles.

As used herein, the term “pharmaceutically effective amount” means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to medical treatment, generally in an amount of 0.001 to 1000 mg / kg, preferably 0.05 to The amount of 200 mg / kg, more preferably 0.1 to 100 mg / kg may be administered once to several times daily. However, for the purposes of the present invention, the specific therapeutically effective amount for a particular patient is determined by the specific composition, including the type and extent of the reaction to be achieved, whether or not other agents are used in some cases, the age, weight, general health of the patient, It is desirable to apply differently depending on various factors and similar factors well known in the medical field, including sex and diet, time of administration, route of administration and rate of composition, duration of treatment, drugs used with or co-specific with the specific composition.

The co-formulation according to the present invention may further comprise a separate pharmaceutically active ingredient.

The formulations of the present invention may comprise a powdered form, preferably in the form of a solid form, but is not impossible to prepare in the form of a liquid, it is not excluded from the scope.

The formulations of the present invention may be administered as individual therapeutic agents or in combination with other therapeutic agents and may be administered sequentially or simultaneously with conventional therapeutic agents. And single or multiple administrations.

As used herein, the term "administration" refers to the introduction of the pharmaceutical composition of the present invention to a patient in any suitable manner, and the route of administration of the composition of the present invention may be varied orally or parenterally as long as the target tissue can be reached. It can be administered via the route. Preferably oral administration. The preparations according to the invention can be prepared in various formulations depending on the mode of administration desired. In one embodiment, the co-formulation may be in capsule form and may be a hard capsule. The capsule material is gelatin or HPMC, more preferably HPMC.

Administration can be effected prophylactically or therapeutically.

The frequency of administration of the formulation of the present invention is not particularly limited, but may be administered once a day or several times in divided doses.

An individual subject to administration of the agent according to the present invention may mean all animals including humans. The animal may be a mammal such as, but not limited to, a human, a cow, a horse, a sheep, a pig, a goat, a camel, a antelope, a dog, a cat, and the like, which require treatment of similar symptoms.

The co-formulation of the present invention maintains stability during storage and distribution, and can prevent the dissolution delay of clopidogrel caused by including clopidogrel tablets in capsules by increasing the disintegration rate of clopidogrel tablets. In addition, the tablet is prepared by mixing colloidal silicon oxide with the main component before adding other additives, and sticking to the punch during tableting as the content ratio of the main component clopidogrel, its isomer or pharmaceutically acceptable salt thereof is increased. Sticking and capping can be prevented from occurring. In addition, the present invention can solve the problems caused when including the tablet in the capsule.

The co-formulation of the present invention is designed to prevent direct contact between the active ingredient clopidogrel and aspirin, thereby blocking the eutectic phenomenon of the two components. In addition, by preventing the change in the physicochemical properties of each component by eliminating eutectic phenomena, it is effective to prevent changes in the content, dissolution characteristics, and bioequivalence of the formulations in the short term, and improve the stability of the formulations in the long term. .

In addition, the combination preparation of the present invention coated aspirin with an enteric layer so that aspirin elutes only in the intestine and does not elute in the stomach, in order to prevent the problem of aspirin irritating the stomach wall and causing damage. Therefore, oral administration of the combination preparation of the present invention, clopidogrel is eluted from the stomach first, aspirin is eluted later in the intestine has the effect of preventing gastric wall damage.

Furthermore, compared to taking clopidogrel and aspirin at the same time or at different time intervals, the convenience and compliance can be increased. It can show the result, there is an advantage of reducing side effects and manufacturing costs by pharmacological components.

Hereinafter, the present invention will be described in detail by the following examples. However, the following examples are only for illustrating the present invention, and the scope of the present invention is not limited by the following examples.

Comparative example  1 and 2

Clopidogrel hydrogen sulfate and PEG 6000, mannitol 300 DC, MCC 102 and L-HPC were mixed in the amounts shown in Table 1 below. The content of Table 1 shows the content per tablet. Next, the mixture was mixed with colloidal silicon dioxide, talc, and sodium stearyl fumarate (PRUV®), followed by tableting. As a result, sticking and capping phenomenon occurred during tableting.

function	Name	Comparative Example 1	Comparative Example 2
		1T (mg)	1T (mg)
chief ingredient	Clopidogrel Sulfate (as Clopidogrel, 75 mg)	97.875	97.875
Excipient	PEG 6000	14.500	7.500
Excipient	Mannitol 300 DC	42.625	43.625
Excipient	MCC 102	25.00	25.00
Excipient	L-HPC	10.00	16.00
Excipient	Colloidal silicon dioxide (colloidal silicon oxide)	2.00	2.00
Lubricant	Talc	4.00	4.00
Lubricant	PRUV®	4.00	4.00
synthesis		200.00	200.00

Example  One

Tablets were prepared according to the ingredients and contents in Table 2 below. Clopidogrel hydrogen sulfate and colloidal silicon dioxide were first mixed, and then the mixture was post-mixed with PEG 6000, mannitol 300 DC, MCC 102, and L-HPC. Thereafter, the lubricant talc and PRUV® were added, followed by tableting. Table 2 shows the content per tablet. In this case, unlike the Comparative Examples 1 and 2 using post-mixing colloidal silicon dioxide and using MCC 102, the tablet of Example 1 did not cause sticking or capping at the time of tableting. The content of the components is shown in Table 2 below.

	Name	Example 1
		1T (mg)
chief ingredient	Clopidogrel Sulfate	97.875
Excipient	PEG 6000	7.600
Excipient	Mannitol 300 DC	38.525
Excipient	MCC 102	21.00
Excipient	L-HPC	17.00
Excipient	Colloidal silicon dioxide	10.00
Lubricant	Talc	4.00
Lubricant	PRUV®	4.00

Example  2 to 7

In order to further improve sticking and capping disorders during tableting, a low drying loss (1.5 wt%) MCC112 was used. Clopidogrel hydrogen sulfate and colloidal silicon dioxide were first mixed, followed by post-mixing of the mixture with PEG 6000, mannitol 300 DC, MCC 112, L-HPC, CL-PVP and PVP K-30. Thereafter, the lubricant, PRUV® was added, followed by tableting. The content of the components is shown in Table 3, respectively. Table 3 shows the content per tablet.

function	Ingredient Name	Example 2	Example 3	Example 4	Example 5	Example 6	Example 7
		1T (mg)	1T (mg)	1T (mg)	1T (mg)	1T (mg)	1T (mg)
chief ingredient	Clopidogrel Sulfate	97.875	97.875	97.875	97.875	97.875	97.875
Excipient	PEG6000	7.600	7.600	7.600	7.600	7.600	7.600
Excipient	Manitol 300 DC	30.725	31.525	31.525	31.525	31.525	31.525
Excipient	MCC 112	17.8	18.00	18.00	18.00	18.00	17.00
Excipient	L-HPC	13.00	17.00	16.00	17.00	15.00	12.00
Disintegrant	CL-PVP	12.00	8.00	5.00	6.00	10.00	16.00
Excipient	Colloidal silicon dioxide	15.00	12.00	16.00	14.00	12.00	12.00
Binder	PVP K-30	2.00	4.00	4.00	4.00	4.00	2.00
Lubricant	PRUV®	4.00	4.00	4.00	4.00	4.00	4.00
synthesis		200.00	200.00	200.00	200.00	200.00	200.00

Example  8 to 10 and Comparative example  3 to 6

In order to understand the effect of colloidal silicon dioxide on the formulation of the present invention including a disintegrant, a tablet having a composition of Table 4 was prepared by varying the content of colloidal silicon dioxide mainly from Examples 2 to 7.

function	Ingredient Name	Comparative example  3	Comparative example  4	Example  8	Example  9	Example  10	Comparative example  5	Comparative example  6
		1T (mg)	1T (mg)	1T (mg)	1T (mg)	1T (mg)	1T (mg)	1T (mg)
chief ingredient	Clopidogrel Sulfate	97.875	97.875	97.875	97.875	97.875	97.875	97.875
Excipient	PEG6000	7.600	7.600	7.600	7.600	7.600	7.600	7.600
Excipient	Manitol 300 DC	40.525	31.525	25.525	28.525	23.525	21.525	15.525
Excipient	MCC 112	20.00	20.00	20.00	18.00	15.00	17.00	15.00
Excipient	L-HPC	20.00	25.00	25.00	10.00	24.00	18.00	30.00
Disintegrant	CL-PVP	8.00	8.00	10.00	12.00	8.00	12.00	8.00
Excipient	Colloidal Silicon Dioxa Id	2.00 ( 1 wt% )	2.00 ( 1 wt% )	6.00 ( 3 wt% )	20.00 ( 10% by weight )	20.00 ( 10% by weight )	22.00 ( 11 wt% )	22.00 ( 11 wt% )
Binder	PVP K-30	4.00	4.00	4.00	2.00	4.00	4.00	4.00
Lubricant	PRUV		4.00	4.00	4.00
synthesis		200.0	200.00	200.0	200.00	200.00	200.00	200.00

Experimental Example  One. Example  2 to 7 Disintegration  exam

Disintegration test was performed on the tablets prepared in Examples 2 to 7 above. Disintegration test was in accordance with the disintegration test method of the Korean Pharmacopoeia General Test Methods (Test Solution: Water). The results were as shown in Table 5 below, and the Plavix tablet was used as a control. In Examples 2 to 7, the disintegration time appears within 11 minutes, it can be seen that the disintegration time is shorter than the control. In Examples 2 to 7 tableting was possible without a tableting disorder.

	Flavix tablet	Example 2	Example 3	Example 4	Example 5	Example 6	Example 7
Disintegration time (minutes)	12	7	8	11	9	7	5

Experimental Example  2. Example  8 to 10 and Comparative example  3 to 6 Disintegration Test  And Capping Sticking  Check whether the test

With the clopidogrel tablets of Examples 8 to 10 and Comparative Examples 3 to 6 described in Table 4, the results of sticking, capping experiments and disintegration time experiments (using the same method as Experimental Example 1 of the present application) are shown in Table 6 below. .

	Comparative example  3	Comparative example  4	Example  8	Example  9	Example  10	Comparative example  5	Comparative example  6
Sticking	X	X	○	○	○	○	○
Capping	X	○	○	○	○	X	○
Disintegration  Minutes	6	-	10	10	7	11	15

(※ when sticking or capping occurs: marked with X; when there is no sticking or capping failure: marked with ○; marked with-at disintegration time indicates that no measurement was made)

In Comparative Examples 3 and 4 in which colloidal silicon oxide was used in an amount of 1% by weight based on the total weight of clopidogrel tablets, sticking and / or capping disorders occurred during tableting, and in addition, 11% by weight of colloidal silicon oxide was used in Comparative Example 5 In the case of the capping failure occurred, in the case of Comparative Example 6 it was confirmed that the disintegration time was very large value of 15 minutes.

On the other hand, Examples 8 to 10 using clavogenic silicon oxide using 3 or 10% by weight based on the total weight of clopidogrel tablets showed disintegration time within 11 minutes without sticking and capping.

These results indicate that tablets containing disintegrant and colloidal silicon dioxide at 2 to 10% by weight, based on the total weight of clopidogrel tablets, have a short disintegration time and can be well compressed at the same time. .

Formulation example  One

-Clopidogrel Sulfate Coating Tablet

0.5 mg of hydroxypropyl cellulose and 3.5 mg of neocoat 8038HP per tablet, an organic solvent of methylene chloride (5% by weight in organic solvent) and ethanol (99.5% by weight in organic solvent) were mixed to prepare a film coating solution. The clopidogrel sulfate uncoated tablet prepared in Example 3 was coated.

-Aspirin Granules Manufacturing

Separately, 100 mg of aspirin (Rhodia, Thailand) and 5.0 mg of hydroxypropylmethylcellulose (Shin-Etsu, Japan) were dissolved in a mixed solvent of 600 mg of methylene chloride and 300 mg of ethanol per capsule, followed by an average particle diameter of 600 to 710 μm. 30 mg of spherical white sugar (IPS, Italy) granules were sprayed with a fluidized bed coater (Glatt GmbH Process Technology, Germany) to form the aspirin nucleus. Subsequently, 9.5 mg of hydroxypropyl methyl cellulose phthalate (Shin-Etsu, Japan, substitution degree 200731, viscosity 40 mPa.s) and hydroxypropyl methyl cellulose (substitution degree 2910, viscosity 15 mPa) were mixed with a mixed solvent of 250 mg of methylene chloride and 250 mg of ethanol. s) Aspirin granules were prepared by dissolving 5 mg and 0.5 mg of triethyl citrate (Morimurabros.INC, Japan) and then spraying the aspirin outer core to form an enteric layer.

204 mg of clopidogrel tablets and 145 mg of aspirin granules were filled into gelatin and HPMC hard capsules, respectively, to prepare a combination formulation including 75 mg of clopidogrel and 100 mg of aspirin.

Formulation example  2

In the same manner as in Preparation Example 1, but using the clopidogrel sulfate uncoated tablet prepared in Example 3, the aspirin granules in the preparation of the contents of the following components, unlike in Preparation Example 1, as shown in Table 7, clopidogrel tablets 75mg and 75mg aspirin 75mg To prepare a composite formulation comprising a.

function	Name	Formulation Example 2
		1T (mg)
chief ingredient	aspirin	75
Excipient	Spherical sugar	22.5
Plasticizer	Triethyl citrate	0.375
Enteric repellent	Hydroxypropylmethylcellulose phthalate (substitution degree 200731, viscosity 40mPa.s)	7.125
Binder	Hydroxypropylmethylcellulose (substitution degree 2910, viscosity 15mPa.s)	3.75

Comparative Example  One

Preparation of Clopidogrel Granules

Dissolve 97.875 mg of clopidogrel hydrogen sulfate and 25.5 mg of hydroxypropylmethylcellulose with 300 mg of anhydrous ethanol and 1000 mg of methylene chloride as a solvent, and then to 103.625 mg of spherical white sugar (IPS, Italy) granules having an average particle diameter of 600 to 710 μm. The mixture was sprayed with a fluid bed coater (Glatt GmbH Process Technology, Germany) to form clopidogrel outer cores. Subsequently, 20 mg of hydroxypropylmethylcellulose and 3.0 mg of polyethylene glycol were dissolved in 200 mg of anhydrous ethanol and 500 mg of methylene chloride, and then sprayed on the clopidogrel outer core to form an immediate protective layer, thereby preparing clopidogrel granules.

-Aspirin Granules Manufacturing

It was prepared in the same manner as the aspirin granules of Preparation Example 1.

Thereafter, 245 mg of clopidogrel tablets and 145 mg of aspirin granules prepared above were filled into gelatin and HPMC hard capsules, respectively, to prepare a combination formulation including 75 mg of clopidogrel and 100 mg of aspirin.

Experimental Example  3. Change of appearance  exam

Using the co-formulation prepared in Formulation Example 1, the capsule was divided into gelatin and HPMC, and subjected to a harsh test by exposure to test conditions at 40 ° C. and 75% RH to observe changes in properties. The results are shown in Table 8 below (O: good state, X: bad state).

Capsule	0 days	1 day	2 days	4 days	7 days	14 days	21st
gelatin	O	O	O	X	X	X	X
HPMC	O	O	O	O	O	O	O

In the harsh test, no change in appearance was observed until 4 days in the gelatin capsule, and no change in appearance was observed even after more than 21 days in the HPMC capsule, which showed more stability than the gelatin capsule.

Experimental Example  4. Stability Test

The composite formulation of the present invention prepared in Preparation Example 1 was subjected to a 6 month accelerated test (temperature 40 ° C., 75% RH PE bottle) to evaluate the stability, and the evaluation results are shown in Table 9 below.

In the case of Formulation Example 1 and Comparative Formulation Example 1, the total amount of the flexible substance was remarkable with time, but in Formulation Example 1, the increase in the flexible substance was significantly decreased.

Time product	0 days	2 months	4 months	6 months
Comparative Example 1	0.933%	1.055%	1.186%	1.520%
Formulation Example 1	0.432%	0.542%	0.564%	0.621%

From the above description, those skilled in the art will appreciate that the present invention can be implemented in other specific forms without changing the technical spirit or essential features. In this regard, the embodiments described above are to be understood in all respects as illustrative and not restrictive. The scope of the present invention should be construed that all changes or modifications derived from the meaning and scope of the following claims and equivalent concepts rather than the detailed description are included in the scope of the present invention.

Claims (16)

1. Clopidogrel tablets comprising clopidogrel, isomers thereof or pharmaceutically acceptable salts thereof; And

   Aspirin core comprising aspirin, an isomer thereof, or a pharmaceutically acceptable salt thereof, and aspirin-containing particles comprising an enteric coating layer surrounding the core.
2. The combination formulation of claim 1, wherein the clopidogrel tablet further comprises a disintegrant.
3. The combination preparation according to claim 2, wherein the disintegrant is contained in an amount of 2 to 8% by weight based on the total weight of the clopidogrel tablet.
4. The method of claim 2,

   The disintegrant is sodium starch glycolate, corn starch, potato starch, starch gelatinized starch, bentonite, montmorillonite, veegum, microcrystalline cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, sodium alginate, alginic acid, croscarmell It is one or more selected from the group consisting of sodium ross (croscarmellose), guar gum, xanthan gum, cross-linked polyvinylpyrrolidone (crospovidone) and mixtures thereof.
5. The combination preparation of claim 1, wherein the clopidogrel tablet further comprises an excipient having a weight loss of 5% by weight or less.
6. The combination preparation according to claim 5, wherein the clopidogrel tablet further comprises an excipient having a drying loss of 1.5 wt% or less.
7. The combination according to claim 5, wherein the excipient is microcrystalline cellulose.
8. The combination formulation of claim 1, wherein the clopidogrel tablet further comprises colloidal silicon oxide.
9. According to claim 8, wherein the content of the colloidal silicon oxide is 2 to 10% by weight based on the total weight of clopidogrel tablets, combination formulation.
10. The method of claim 1,

    The enteric coating layer may be shellac, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, cellulose acetate phthalate, cellulose acetate, polyvinyl alcohol phthalate, methacrylic acid-methylmethacrylic acid copolymer, methylacrylic acid-methylmethacrylate. A composite formulation comprising at least one enteric coating agent selected from the group consisting of methacrylic acid-methacrylic acid copolymer, methacrylic acid-ethylacrylic acid copolymer, and mixtures thereof.
11. The co-formulation according to any one of claims 1 to 10, wherein the co-formulation is a capsule formulation.
12. The combination according to claim 11, wherein the capsule is made of gelatin or hydroxypropyl methylcellulose (HPMC).
13. The combination formulation of claim 1, wherein the clopidogrel tablet has a disintegration time of less than 11 minutes.
14. Preparing clopidogrel tablets by first mixing clopidogrel, an isomer thereof or a pharmaceutically acceptable salt thereof, and colloidal silicon oxide, followed by the addition of a disintegrant;

    Preparing an aspirin core comprising an aspirin, an isomer thereof or a pharmaceutically acceptable salt thereof; And

    Clopidogrel tablet and aspirin core comprising the step of coating the aspirin core with an enteric coating, a method for producing a composite formulation comprising aspirin core.
15. The method of claim 14, wherein the disintegrant is included in an amount of 2 to 8 wt% based on the total weight of the clopidogrel tablet.
16. The method of claim 14, wherein the content of the colloidal silicon oxide is 2 to 10% by weight based on the total weight of the clopidogrel tablet.