阅读说明：本技术 包含抗血小板剂和胃酸分泌抑制剂的药物组合物 (Pharmaceutical composition comprising antiplatelet agent and gastric acid secretion inhibitor ) 是由 曺泰根 曺永大 权恩智 申明珍 于 2019-08-27 设计创作，主要内容包括：本发明提供了一种药物组合物,其包含：氯吡格雷或其药学上可接受的盐；以及式1化合物或其药学上可接受的盐作为活性成分。本发明的药物组合物具有在预防或治疗氯吡格雷的副作用(即胃肠道病症)的同时维持氯吡格雷药效的优点。(The present invention provides a pharmaceutical composition comprising: clopidogrel or a pharmaceutically acceptable salt thereof; and a compound of formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient. The pharmaceutical composition of the present invention has the advantage of maintaining the pharmacological effects of clopidogrel while preventing or treating the side effects (i.e., gastrointestinal disorders) of clopidogrel.)

1. A pharmaceutical composition comprising: clopidogrel or a pharmaceutically acceptable salt thereof; and a compound of formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient,

[ formula 1]

2. The pharmaceutical composition of claim 1, wherein clopidogrel or a pharmaceutically acceptable salt thereof is contained in an amount of 10 to 300 mg.

3. The pharmaceutical composition according to claim 1, wherein the content of the compound of formula 1 or the pharmaceutically acceptable salt thereof is 10mg to 200 mg.

4. The pharmaceutical composition of claim 1, wherein the composition is a combined or complex formulation.

5. The pharmaceutical composition of claim 1, wherein the composition is a formulation for oral administration.

6. The pharmaceutical composition of claim 5, wherein the formulation for oral administration is a granular formulation, a pellet formulation, a tablet or a capsule formulation.

7. The pharmaceutical composition of claim 1, wherein the composition further comprises a pharmaceutically acceptable additive.

8. The pharmaceutical composition of claim 1, wherein the composition further comprises one or more additives selected from the group consisting of diluents, disintegrants, binders, pH adjusting agents, glidants, and coating agents.

9. The pharmaceutical composition according to claim 8, wherein the diluent is one or more selected from the group consisting of microcrystalline cellulose, starch, dextrin, lactose, sucrose, mannitol, xylitol, isomalt and sorbitol.

10. The pharmaceutical composition according to claim 8, wherein the disintegrant is one or more selected from the group consisting of sodium starch glycolate, croscarmellose sodium, hydroxypropylcellulose, carboxymethylcellulose, cross-linked polyvinylpyrrolidone, corn starch, or pregelatinized starch.

11. The pharmaceutical composition according to claim 8, wherein the binder and coating agent is one selected from the group consisting of sodium carboxymethylcellulose, ethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, polyvinylpyrrolidone, xanthan gum, sodium alginate and gelatin, or a combination of two or more thereof.

12. The pharmaceutical composition of claim 8, wherein the pH adjusting agent is an organic acid.

13. The pharmaceutical composition according to claim 12, wherein the organic acid is one or more selected from the group consisting of citric acid, tartaric acid, fumaric acid, lactic acid, phosphoric acid and malic acid.

14. The pharmaceutical composition of claim 6, wherein the capsule formulation is filled with particles or pellets comprising clopidogrel or a pharmaceutically acceptable salt thereof.

15. The pharmaceutical composition of claim 6, wherein the capsule formulation is filled with granules or pellets comprising a compound of formula 1 or a pharmaceutically acceptable salt thereof.

16. The pharmaceutical composition of claim 6, wherein the capsule formulation is filled with multi-layer coated pellets having in their inner layers: clopidogrel or a pharmaceutically acceptable salt thereof, and a compound of formula 1 or a pharmaceutically acceptable salt thereof.

17. The pharmaceutical composition of claim 4, wherein the co-formulation does not bring clopidogrel or a pharmaceutically acceptable salt thereof and the compound of formula 1 or a pharmaceutically acceptable salt thereof into direct contact with each other.

18. The pharmaceutical composition according to claim 4, wherein the combination is of the kit type.

19. The pharmaceutical composition according to claim 1, wherein the composition is for antiplatelet therapy.

20. A method for preventing or treating a disease associated with thrombosis, the method comprising the step of administering to a subject in need thereof a pharmaceutical composition comprising: clopidogrel or a pharmaceutically acceptable salt thereof; and a compound of formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient,

[ formula 1]

21. Use of clopidogrel or a pharmaceutically acceptable salt thereof, and a compound of formula 1 or a pharmaceutically acceptable salt thereof for the prevention or treatment of diseases associated with thrombosis,

[ formula 1]

22. Use of clopidogrel or a pharmaceutically acceptable salt thereof, and a compound of formula 1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the prevention or treatment of a disease associated with thrombosis,

[ formula 1]

Technical Field

The present invention relates to a pharmaceutical composition comprising clopidogrel and a compound of formula 1, and more particularly, to a pharmaceutical composition which is sufficiently stable to maintain the pharmacological effects of clopidogrel while preventing or reducing clopidogrel-related gastrointestinal disorders, such that clopidogrel is used in combination with a compound of formula 1.

[ formula 1]

Background

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

Clopidogrel specifically inhibits adenosine diphosphate (hereinafter referred to as "ADP") induced platelet aggregation by directly inhibiting the binding of ADP to an ADP receptor, which is known to play an important role in thrombosis, and then by directly inhibiting ADP-mediated activation of the subsequent glycoprotein GPIIb/IIa complex. In addition, clopidogrel blocks the amplification of platelet activation by released ADP, thereby inhibiting platelet aggregation caused by agonists other than ADP. Upon acting on platelets, clopidogrel shows an effect of inhibiting such aggregation until about seven days, at which time the life span of such platelets is over.

This effect of clopidogrel is the effect performed by the active metabolite of clopidogrel. In other words, enzymes that metabolize clopidogrel in the liver are important factors for clopidogrel effectiveness. In the early days, clopidogrel was predicted to be metabolized only by CYP1A, but CYP2C19 was further found in recent studies to be also used as an enzyme involved in converting clopidogrel into an active metabolite.

Meanwhile, clopidogrel has a problem of side effects because it causes gastrointestinal disorders such as ulcer and gastrointestinal bleeding. Patients who have a long-term need for antiplatelet drug therapy often pause or become ineligible for such therapy due to gastrointestinal disorders. Thus, such patients may not expect a beneficial therapeutic effect.

In order to overcome side effects such as gastrointestinal disorders, clopidogrel and proton pump inhibitors (hereinafter referred to as "PPIs") are, in rare cases, prescribed in combination outside the trademark drug. However, it has been reported from a series of research results that if clopidogrel is administered in combination with a PPI-based drug (e.g., omeprazole, esomeprazole, pantoprazole, lansoprazole, etc.) that inhibits CYP2C19 activity, the drug concentration of clopidogrel active metabolites becomes low enough to reduce the drug efficacy thereof by half. This is because clopidogrel is characterized by having a mechanism in which clopidogrel is converted into an active metabolite via CYP2C19, thereby exhibiting drug efficacy.

Thus, the us FDA in 2011 recommended that clopidogrel not be used with omeprazole. This measure is taken to reflect the clinical outcome in which the co-ingestion of certain PPIs interferes with the effect of clopidogrel, thereby increasing the risk of cardiac events such as acute myocardial infarction and the like.

Against these backgrounds, as a result of efforts to find a method for overcoming gastrointestinal disorders while ensuring the original pharmacological effects of clopidogrel, the present inventors have determined that the combined use of clopidogrel with the compound of formula 1 can surprisingly restore the inhibited pharmacological effects of clopidogrel, i.e., solve the problems of the existing inhibitors of gastric acid secretion, while preventing and treating gastrointestinal disorders caused by clopidogrel, thereby completing the present invention.

[ Prior Art reference ]

Prior art reference 1: korean patent laid-open No. 10-2008-0112361 "Oral document for enclosing an anti-latelet agent and an acid inhibitor"

Prior art reference 2: korean patent laid-open No. 10-2015- "

Prior art reference 3: korean patent registration No. 10-1088247, "Chroman Substitted bed zimidazoles and use of as acid pump inhibitors"

Prior art reference 4: U.S. Pat. No. 2015/0079169 "Controlled forcing of cloning with organic acid inhibition therapeutics"

[ non-patent document ]

Non-patent document 1: "Cytochrome P4502C 19 loss-of-function polyraphism is a major determinant of cloning responsiveness in health subjects," Jean-Sebastein et al, The American Society of Hematology, Blood,2006, 10/1/2006. Volume 108, No. 7.

Non-patent document 2: effect of the proton pump inhibitors on the drug interactions additives, safe productive by the Korean Journal of Internal Medicine, volume 81, first term 2011.

Disclosure of Invention

Technical problem

The present invention provides a pharmaceutical composition comprising: clopidogrel or a pharmaceutically acceptable salt thereof; and a compound of formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

[ formula 1]

The present invention provides a method for preventing or treating a disease associated with thrombosis, the method comprising the step of administering to a subject in need thereof a pharmaceutical composition comprising: clopidogrel or a pharmaceutically acceptable salt thereof; and a compound of formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

The present invention provides clopidogrel or a pharmaceutically acceptable salt thereof, and the use of a compound of formula 1 or a pharmaceutically acceptable salt thereof for the prevention or treatment of diseases associated with thrombosis.

The invention provides clopidogrel or a pharmaceutically acceptable salt thereof, and a compound of formula 1 or a pharmaceutically acceptable salt thereof for use in the preparation of a medicament for the prevention or treatment of a disease associated with thrombosis.

Technical scheme

The specific description is as follows. Meanwhile, each description and embodiment disclosed in the present invention may be applied to other descriptions and embodiments, respectively. In other words, all combinations of the various elements disclosed in the present invention fall within the scope of the present invention. In addition, it is to be understood that the scope of the invention is not to be limited by the specific details described below.

According to an aspect of the present invention, to achieve the above objects, there is provided a pharmaceutical composition comprising: clopidogrel or a pharmaceutically acceptable salt thereof; and a compound of formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

[ formula 1]

The pharmaceutical composition may be a pharmaceutical composition comprising clopidogrel or a pharmaceutically acceptable salt thereof, and the compound of formula 1 or a pharmaceutically acceptable salt thereof, as a single preparation or a combined preparation, respectively. In other words, the pharmaceutical composition may be a combination of single or multiple formulations. In the case of using a combination of clopidogrel or a pharmaceutically acceptable salt thereof and the compound of formula 1 or a pharmaceutically acceptable salt thereof, the pharmaceutical effect of clopidogrel or a pharmaceutically acceptable salt thereof can be maintained while gastrointestinal disorders resulting therefrom can be prevented or treated. Therefore, the pharmaceutical composition has an excellent effect on all diseases known to be prevented or treated by conventional clopidogrel. The pharmaceutical composition can be used very valuable as a composition for, for example, antiplatelet therapy. In addition, a pharmaceutical composition comprising a compound of formula 1 or a pharmaceutically acceptable salt thereof may be very valuable for the purpose of preventing or treating gastrointestinal disorders associated with antiplatelet therapy (e.g., gastrointestinal disorders due to administration of clopidogrel).

According to one embodiment of the invention, the pharmaceutical composition of the invention may be a formulation for oral administration. Formulations for oral administration may be formulated as capsule formulations (including soft and hard capsule formulations); tablets (including mono-layer tablets, multi-layer tablets, and gastrodisintegrative, effervescent, and modified release dosage forms); a granular formulation; a pellet formulation; a solvent; a suspension; powder; gelling; a film for oral administration; or other dosage forms known in the art.

According to another embodiment of the present invention, in the pharmaceutical composition of the present invention, the clopidogrel or a pharmaceutically acceptable salt thereof may be contained in an amount of 10 to 300 mg.

According to another embodiment of the present invention, the content of the compound of formula 1 in the pharmaceutical composition of the present invention may be 10 to 200 mg.

The pharmaceutical compositions of the present invention can be described in more detail as follows.

(1) Active ingredient

As used herein, the term "clopidogrel" refers to methyl (+) - (S) - α - (2-chlorophenyl) -6, 7-dihydrothieno [3,2-c ] pyridine-5 (4H) -acetate, and is particularly represented by the following formula X. Clopidogrel is effective as an antiplatelet agent for the treatment of peripheral or coronary artery disease, such as stroke, thrombosis, embolism, or myocardial infarction.

[ formula X ]

Clopidogrel directly inhibits the binding of adenosine diphosphate (hereinafter referred to as "ADP") to an ADP receptor, which is known to play an important role in thrombosis. In addition, clopidogrel specifically inhibits ADP-induced platelet aggregation by directly inhibiting ADP-mediated activation of the subsequent glycoprotein GPIIb/IIa complex. In addition, clopidogrel blocks the amplification of platelet activation by released ADP, thereby inhibiting platelet aggregation caused by agonists other than ADP.

According to an embodiment of the present invention, the pharmaceutically acceptable salt of clopidogrel may be selected from the group consisting of clopidogrel hydrogen sulfate, resinate, camphorsulfonate, benzenesulfonate, napadisylate monohydrate, hydrochloride, and a mixture thereof, but is not limited thereto.

In the pharmaceutical composition of the present invention, the content of clopidogrel or a pharmaceutically acceptable salt thereof may be 10 to 300mg, preferably 75 to 300mg, but is not limited thereto.

As used herein, the term "compound of formula 1" refers to ((S) -4- [ (5, 7-difluoro-3, 4-dihydro-2H-chromen-4-yl) oxy ] -N, 2-trimethyl-1H-benzimidazole-6-carboxamide), particularly represented by formula 1 below, and is referred to as tegolazan.

[ formula 1]

In the case of the compound of formula 1 above, the compound or a pharmaceutically acceptable salt thereof, and optical isomers and racemates showing equivalent efficacy thereto are included in the scope herein.

The above compounds of formula 1 are useful as gastric acid secretion inhibitors for the treatment of diseases mediated by acid pump antagonistic activity, such as gastrointestinal diseases, gastroesophageal reflux disease (GERD), peptic ulcer, gastric ulcer, duodenal ulcer, NSAID-induced ulcer, gastritis, helicobacter pylori infection, dyspepsia, functional dyspepsia, zollinger-ellison syndrome, non-erosive reflux disease (NERD), visceral involve pain, pus, nausea, esophagitis, dysphagia, sialorrhea, airway injury or asthma, wherein eligible diseases are not limited to the above listed diseases. The compound of formula 1 according to the present invention is a potassium competitive acid blocker (P-CAB).

According to one embodiment of the present invention, the pharmaceutically acceptable salts of the above compounds of formula 1 may comprise acid addition salts and base addition salts (including dibasic bases). The acid addition salts may be, for example, acetate, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate/carbonate, bisulfate/sulfate, borate, camphorsulfonate, citrate, cyclamate, edisylate, ethanesulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, hyacinate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, methanesulfonate, methylsulfate, naproxate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate, dihydrogenphosphate, dihydrogensulfate, gluconate, glucuronate, hexafluorophosphate, hexamate, hexafluohnate, hyacin, Sucrose salts, stearates, succinates, tannates, tartrates, tosylates, trifluoroacetates or xinafoates, but are not limited thereto. Base addition salts may be, for example, alkali metal salts, such as lithium, sodium or potassium salts; alkaline earth metal salts, such as calcium or magnesium salts; an ammonium salt; or an organic basic salt such as triethylamine salt, diisopropylamine salt or cyclohexylamine salt, but not limited thereto.

(2) Dosage forms and administration

The pharmaceutical composition of the present invention can be used in such a manner that such composition is formulated into various forms according to a conventional method suitable for the purpose of use, such as preparations for oral administration, e.g., powders, granular preparations, pellet preparations, tablets, capsule preparations, suspensions, emulsions, syrups, aerosols, etc.; formulations for injection of sterile injectable solutions; and so on.

According to one embodiment of the invention, the pharmaceutical composition of the invention is a formulation for oral administration. Further, according to a preferred embodiment of the present invention, the formulation for oral administration is selected from a granular formulation, a pellet formulation, a tablet or a capsule formulation.

According to a preferred embodiment of the present invention, these capsule formulations may be formulations filled with granules or pellets containing clopidogrel or a pharmaceutically acceptable salt thereof. In addition, according to a preferred embodiment of the present invention, these capsule formulations may be formulations filled with granules or pellets containing the compound of formula 1 or a pharmaceutically acceptable salt thereof. According to another preferred embodiment of the present invention, the capsule formulations may be formulations filled with multi-layered coated pellets having one of clopidogrel or a pharmaceutically acceptable salt thereof and the compound of formula 1 or a pharmaceutically acceptable salt thereof in the inner layer thereof.

According to a specific embodiment of the present invention, these capsule formulations are filled with pellets comprising clopidogrel or a pharmaceutically acceptable salt thereof, and granules comprising the compound of formula 1 or a pharmaceutically acceptable salt thereof.

According to another embodiment of the present invention, the capsule formulations are filled with pellets comprising clopidogrel or a pharmaceutically acceptable salt thereof and the compound of formula 1 or a pharmaceutically acceptable salt thereof. These pellets may contain all of clopidogrel or a pharmaceutically acceptable salt thereof and the compound of formula 1 or a pharmaceutically acceptable salt thereof in one granule, and may also contain only one of clopidogrel or a pharmaceutically acceptable salt thereof and the compound of formula 1 or a pharmaceutically acceptable salt thereof in one granule, respectively.

According to one embodiment of the invention, the tablets may be single-layer tablets or multilayer tablets. A multilayer tablet may be, for example, a two-layer tablet or a three-layer tablet, and wherein there may be a layer that does not contain an active ingredient.

According to one embodiment of the present invention, clopidogrel or a pharmaceutically acceptable salt thereof and the compound of formula 1 or a pharmaceutically acceptable salt thereof may be prepared in a form that does not need to be in direct physical contact with each other. Such blocking of physical contact may make it more advantageous to ensure stability, for example in a manner that minimizes production of related substances by controlling physicochemical reactions or interactions between drugs.

According to one embodiment of the present invention, a combination comprising clopidogrel or a pharmaceutically acceptable salt thereof and the compound of formula 1 or a pharmaceutically acceptable salt thereof may be formed in the form of a kit. The kit comprises separate preparations each containing an active ingredient, and may optionally contain other elements, for example, additional reagents or user manuals, etc.

The pharmaceutical composition of the present invention may further comprise other antiplatelet agents as active ingredients, in addition to clopidogrel or a pharmaceutically acceptable salt thereof, and the compound of formula 1 or a pharmaceutically acceptable salt thereof. In addition, the pharmaceutical compositions of the present invention may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered in a single or multiple manner.

In the present invention, "administration" means providing a subject with an active ingredient in any suitable way, and the pharmaceutical composition of the present invention can be administered via all general routes as long as such composition can reach a target tissue. In addition, the compositions of the present invention may be administered with any device capable of delivering the active ingredient to the target organ.

In the present invention, the "subject" includes mammals such as humans, guinea pigs, monkeys, cows, horses, sheep, pigs, chickens, turkeys, quails, cats, dogs, mice, rats, or rabbits, but is not limited thereto, and may preferably be humans.

(3) Pharmaceutically acceptable additives

The pharmaceutical composition of the present invention may further comprise pharmaceutically acceptable additives within a range that does not impair the effects of the active ingredient according to the present invention. As additives, any pharmaceutically acceptable substance conventionally used in each dosage form may also be used, for example, fillers, disintegrants, binders, plasticizers, glidants, coating agents (for moisture resistance or enteric properties), pH adjusting agents, diluents, lubricants, preservatives, buffers, sweeteners, wetting agents, suspending agents, colorants, flavors, excipients, and the like.

According to a specific embodiment of the present invention, the granules or pellets comprising clopidogrel or a pharmaceutically acceptable salt thereof comprise a pharmaceutically acceptable filler, a disintegrant, a binder, a plasticizer, a glidant, a coating agent and a pH adjusting agent.

According to a specific embodiment of the present invention, the granules or pellets comprising a compound of formula 1 or a pharmaceutically acceptable salt thereof comprise a pharmaceutically acceptable binder, a disintegrant and a glidant.

The granules or pellets may be administered in the form of a granule formulation or pellet formulation, respectively, and may also be administered in a manner that the granules or pellets are filled into capsules or the granules or pellets are compressed and formulated into tablets.

In the present invention, as the filler, the following can be used, but not limited thereto: microcrystalline cellulose, methylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, propylene glycol, lactose, white sugar, glucose, fructose, dextrin, mannitol, sodium alginate, corn starch, potato starch, pregelatinized starch, hydroxypropyl starch, precipitated calcium carbonate, synthetic aluminum silicate, calcium hydrogen phosphate, calcium sulfate, sodium chloride, sodium bicarbonate, purified lanolin, kaolin, urea, colloidal silica gel, casein, sodium carboxymethyl starch, or a mixture thereof.

According to a preferred embodiment of the present invention, in the granules or pellets comprising clopidogrel or a pharmaceutically acceptable salt thereof, the filler may be selected from the group consisting of microcrystalline cellulose, methylcellulose, sodium carboxymethylcellulose, lactose, dextrin, mannitol, white sugar, corn starch, pregelatinized starch, precipitated calcium carbonate and calcium hydrogen phosphate, or a mixture thereof.

In the present invention, as the disintegrant, the following can be used, but not limited thereto: guar gum, xanthan gum, sodium starch glycolate, low-substituted hydroxypropyl cellulose, croscarmellose sodium, microcrystalline cellulose, crospovidone, corn starch, gelatinized starch, dextran, mannitol, sodium and calcium carboxymethylcellulose, sodium or alginic acid, magnesium aluminum silicate, silicic anhydride, bentonite, montmorillonite, magnesium aluminum silicate, sodium bicarbonate, citric acid, carboxymethyl cellulose, cross-linked polyvinylpyrrolidone, pregelatinized starch, or a mixture thereof, and the like.

According to a preferred embodiment of the present invention, the disintegrant may be selected from sodium starch glycolate, croscarmellose sodium, hydroxypropylcellulose, carboxymethylcellulose, crospovidone, corn starch, or pregelatinized starch.

According to a preferred embodiment of the present invention, in the granules or pellets comprising clopidogrel or a pharmaceutically acceptable salt thereof, the disintegrant may be selected from the group consisting of guar gum, xanthan gum, sodium starch glycolate, low-substituted hydroxypropyl cellulose, croscarmellose sodium, corn starch, gelatinized starch, dextran, carboxymethylcellulose sodium and carboxymethylcellulose calcium, magnesium aluminum silicate and silicic anhydride, and mixtures thereof.

According to a preferred embodiment of the present invention, in the granules or pellets comprising the compound of formula 1 or a pharmaceutically acceptable salt thereof, the disintegrant may be selected from sodium starch glycolate, corn starch, bentonite, guar gum, xanthan gum, sodium or alginic acid, low-substituted hydroxypropylcellulose, microcrystalline cellulose, mannitol, magnesium aluminum silicate, croscarmellose sodium (e.g., Ac-Di-) Crosslinked polyvinylpyrrolidone and mixtures thereof.

In the present invention, as the binder, the following may be used, but not limited thereto: alginic acid, sodium alginate, carbomer, copovidone, starch, pregelatinized starch, polyethylene glycol, polyvinylpyrrolidone copolymer, polyethylene derivative, microcrystalline cellulose, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose and its salt, gelatin, acacia, sodium caseinate, dextrin, mannitol, lactose, xanthan gum, colloidal silicon dioxide, or a mixture thereof, and the like.

According to a preferred embodiment of the present invention, in the granules or pellets comprising clopidogrel or a pharmaceutically acceptable salt thereof, the binder may be selected from alginic acid, carbomer, copovidone, starch, pregelatinized starch, polyethylene derivatives, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose and salts thereof, gelatin, acacia and sodium caseinate or a mixture thereof.

According to a preferred embodiment of the present invention, in the granules or pellets comprising the compound of formula 1 or a pharmaceutically acceptable salt thereof, the binder may be selected from xanthan gum, sodium alginate, gelatin, gum arabic, dextrin, starch, mannitol, lactose, microcrystalline cellulose, colloidal silicon dioxide, polyethylene glycol, polyvinylpyrrolidone copolymer, hydroxypropyl cellulose, hydroxypropyl methylcellulose, or a mixture thereof.

In the present invention, as the glidant, the following may be used, but not limited thereto: talc, stearic acid and its salts (e.g., calcium stearate, magnesium stearate, or zinc stearate), sodium stearyl fumarate, silica, glyceryl monostearate, polyethylene glycol, sodium benzoate, sodium stearyl fumarate, glyceryl monooleate, glyceryl monostearate, glyceryl behenate, glyceryl palmitostearate, paraffin, or mixtures thereof, and the like.

According to a preferred embodiment of the present invention, in the granules or pellets comprising clopidogrel or a pharmaceutically acceptable salt thereof, the glidant may be selected from talc, stearic acid and salts thereof, sodium stearyl fumarate, silicon dioxide, glyceryl monostearate, polyethylene glycol and mixtures thereof.

According to a preferred embodiment of the present invention, in the granules or pellets comprising the compound of formula 1 or a pharmaceutically acceptable salt thereof, as a glidant, the following may be used, but not limited thereto: stearic acid, calcium stearate, magnesium stearate, sodium benzoate, sodium stearyl fumarate, glyceryl monooleate, glyceryl monostearate, glyceryl behenate, glyceryl palmitostearate, zinc stearate, paraffin, etc.

In the present invention, the plasticizer may be selected from the group consisting of ethylene glycol, esters, acetyl silicone oil, triethyl citrate, glycerin derivatives, and mixtures thereof.

In the present invention, the coating agent may be selected from the group consisting of methylcellulose, ethylcellulose, methylhydroxyethylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, hydroxyethylcellulose, cellulose gum, cellulose acetate butyrate, nitrocellulose, salts thereof, and mixtures thereof.

In the present invention, the pH adjusting agent includes an organic acid, and the organic acid may be selected from the group consisting of citric acid, hydrochloric acid, lactic acid, phosphoric acid, propionic acid, sulfuric acid, tartaric acid, fumaric acid, malic acid, and a mixture thereof.

According to a preferred embodiment of the present invention, the pH adjusting agent may be one or more selected from the group consisting of citric acid, tartaric acid, fumaric acid, lactic acid, phosphoric acid, and malic acid.

In the present invention, the diluent may be selected from starch, lactic acid, white sugar, dextrin, dextrose, microcrystalline cellulose, sodium carboxymethylcellulose, mannitol, sorbitol, xylitol, isomalt, sucrose, dibasic calcium phosphate, colloidal silicon dioxide, or a mixture thereof.

According to a preferred embodiment of the present invention, the diluent may be selected from microcrystalline cellulose, starch, dextrin, lactose, sucrose, mannitol, xylitol, isomalt, sorbitol or mixtures thereof.

According to a preferred embodiment of the present invention, the binder and the coating agent may be one or a combination of two or more selected from the group consisting of sodium carboxymethylcellulose, ethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, polyvinylpyrrolidone, xanthan gum, sodium alginate and gelatin.

The scope of the present invention is not limited to the use of additives, and additives may be included in a conventional dosage range by selection of those skilled in the art.

(4) Method of treatment

The present invention also provides a method for preventing or treating a disease associated with thrombosis in a subject, the method comprising the step of administering to a subject in need thereof a pharmaceutical composition comprising: clopidogrel or a pharmaceutically acceptable salt thereof; and a compound of formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient. The pharmaceutical compositions of the present invention are administered in a pharmaceutically effective amount.

In the present invention, "a disease associated with thrombosis" means a disease possibly caused by vascular occlusion caused by thrombosis, and may refer to stroke, thrombosis, embolism, myocardial infarction, or the like, but is not limited thereto.

In the present invention, "pharmaceutically effective amount" means an amount sufficient to treat a disease at a reasonable benefit/risk ratio applicable to medical treatment, and the level of the effective amount may be determined according to factors including the type of disease, severity, pharmaceutical activity, sensitivity to drugs, administration time, administration route and excretion rate of a patient, treatment period and concomitant use of drugs, and other factors well known in the medical field. In view of all of the above, it is important to administer in an amount wherein the maximum effect can be achieved by a minimum amount without side effects, wherein such amount can be readily determined by one skilled in the art.

The pharmaceutical composition of the present invention may be administered orally or via various routes including intravenous, intraperitoneal, subcutaneous, rectal, topical administration, etc., and may be administered to mammals such as humans, rats, mice, livestock, etc.

Specifically, in the composition of the present invention, the daily dose of clopidogrel or a pharmaceutically acceptable salt thereof is 10 to 300mg, preferably 75 to 300mg, based on an adult. In addition, in the composition of the present invention, the daily dose of the compound of formula 1 or a pharmaceutically acceptable salt thereof is 10 to 200mg based on an adult. However, the scope of the present invention is not limited to this dose.

In the present invention, "prevention" means all behaviors that suppress or delay the occurrence, spread, or recurrence of a disease by administering the composition of the present invention, and "treatment" means all behaviors that make symptoms of a disease better or that make a favorable transition by administering the composition of the present invention.

(5) Therapeutic uses

The present invention provides clopidogrel or a pharmaceutically acceptable salt thereof, and the use of a compound of formula 1 or a pharmaceutically acceptable salt thereof for the prevention or treatment of diseases associated with thrombosis. Clopidogrel or a pharmaceutically acceptable salt thereof, and the compound of formula 1 or a pharmaceutically acceptable salt thereof for the prevention or treatment of diseases associated with thrombosis may be combined with acceptable adjuvants, diluents, carriers, etc., and may be prepared as a complex formulation together with other active agents, thereby having a synergistic effect of the active ingredients.

(6) For the preparation of medicaments

The invention provides clopidogrel or a pharmaceutically acceptable salt thereof, and a compound of formula 1 or a pharmaceutically acceptable salt thereof for use in the preparation of a medicament for the prevention or treatment of a disease associated with thrombosis. In the preparation of a medicament for preventing or treating diseases associated with thrombosis, clopidogrel or a pharmaceutically acceptable salt thereof, and the compound of formula 1 or a pharmaceutically acceptable salt thereof may be combined with acceptable adjuvants, diluents, carriers, etc., and may be prepared as a complex formulation together with other active agents, thereby having a synergistic effect of the active ingredients.

The substances mentioned in the compositions, methods of treatment and uses of the invention apply in the same way if not contradictory to each other.

Advantageous effects of the invention

By using the compound of formula 1 (i.e., gastric acid secretion inhibitor) in combination with clopidogrel, the present invention exhibits the effect of preventing and treating gastrointestinal disorders caused by clopidogrel while maintaining the medicinal effect of clopidogrel.

Drawings

Fig. 1 is a graph showing clopidogrel concentration in blood when clopidogrel is administered in combination with esomeprazole.

Fig. 2 is a graph showing clopidogrel concentration in blood when clopidogrel is administered in combination with the compound of formula 1.

Fig. 3 is a result of testing the blending compatibility with clopidogrel-related substance a.

Fig. 4 is a result of testing the blending compatibility with clopidogrel-related substance C.

Fig. 5 is a result of testing the blending compatibility of the contents of clopidogrel and the compound of formula 1.

Fig. 6 is a graph showing clopidogrel concentration in blood.

FIG. 7 is a graph showing the concentration of the compound of formula 1 in blood.

Fig. 8 is a graph showing clopidogrel elution at pH 4.0.

Fig. 9 is a graph showing elution of clopidogrel in water.

Fig. 10 is a graph showing elution of the compound of formula 1 at pH 4.0.

Fig. 11 is a graph showing the elution of the compound of formula 1 in water.

Detailed Description

Hereinafter, the present invention will be described in more detail by way of exemplary embodiments. However, these exemplary embodiments are provided only for the purpose of illustrating the present invention, and thus the scope of the present invention is not limited thereto.

Example 1: capsules containing clopidogrel pellets together with granules of the compound of formula 1

A. Preparation of clopidogrel pellets

Clopidogrel pellets were prepared according to the components and contents as shown in table 1 below.

The mixture was prepared in such a manner that tartaric acid, hydroxypropyl cellulose, hydroxypropyl methylcellulose, dimethicone and talc were dissolved in ethanol. Thereafter, pellets were prepared by spraying the mixture onto white sugar spheres using a fluid bed granulator (GPCG-1, Glatt GmbH, Germany). A mixture in which clopidogrel bisulfate, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, triethyl citrate and talc were dissolved in isopropyl alcohol was sprayed onto the pellets prepared above using the same apparatus, thereby preparing clopidogrel pellets.

The coating conditions were as follows: the temperature of the inflow air is 60 + -5 deg.C, the temperature of the exhaust air is 45 + -5 deg.C, the air volume is 40 + -20%, the spray pressure is 1.5 + -0.5 bar, and the spray speed is 10 + -5 g

[ Table 1]

B. Preparation of Compound particles of formula 1

Particles of the compound of formula 1 were prepared according to the components and contents as shown in table 2 below.

The kneading and drying process is performed by mixing the compound of formula 1, mannitol, microcrystalline cellulose and croscarmellose sodium together, and then adding a binder solution comprising hydroxypropyl cellulose and purified water to the resulting mixture. At the end of drying, size adjustment is performed, and then colloidal silicon dioxide and magnesium stearate are mixed together, thereby completing granules of the compound of formula 1.

[ Table 2]

Component name	Amount (mg)
		Compounds of formula 1	50.0
Mannitol	50.0
		Microcrystalline cellulose	80.0
Croscarmellose sodium	10.0
		Hydroxypropyl cellulose	6.0
Colloidal silicon dioxide	2.0
		Magnesium stearate	2.0

233mg of the clopidogrel pellet prepared above and 200mg of the granules of the compound of formula 1 were put into a hard capsule, thereby preparing a capsule formulation of the pharmaceutical composition of the present invention.

Example 2-1: preparation of composite pellets containing clopidogrel and compound of formula 1

Pellets containing clopidogrel hydrogen sulfate and the compound of formula 1 were prepared according to the components and contents as shown in table 3 below.

Pellets were prepared by preparing a mixture in such a manner that tartaric acid, hydroxypropyl cellulose, hydroxypropyl methylcellulose, dimethicone and talc were dissolved in ethanol, and then spraying the resulting mixture on white sugar spheres using a fluid bed granulator (GPCG-1, Glatt GmbH, Germany). Pellets of the compound of formula 1 were prepared by spraying a mixture in which the compound of formula 1, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, triethyl citrate and talc were dissolved in isopropanol and ethanol onto the pellets prepared above using the same apparatus. Clopidogrel hydrogen sulfate, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, triethyl citrate, and talc were dissolved in isopropyl alcohol to prepare a coating solution. Composite pellets comprising clopidogrel and the compound of formula 1 are prepared by coating pellets of the compound of formula 1 prepared above with a coating solution using a fluid bed granulator.

The coating was performed under the same conditions as shown in example 1.

[ Table 3]

Component name	Amount (mg)
		White sugar ball	50.0
Clopidogrel hydrogen sulfate	97.875
		Compounds of formula 1	50.0
Tartaric acid	50.0
		Hydroxypropyl cellulose	22.5
Talc	7.625
		Hydroxypropyl methylcellulose	14.7
Polydimethylsiloxane	0.6
		Citric acid triethyl ester	1.7

Example 2-2: preparation of composite pellets containing clopidogrel and compound of formula 1

Pellets containing clopidogrel hydrogen sulfate and the compound of formula 1 were prepared according to the components and contents as shown in table 4 below.

The coating solution was prepared by dissolving the compound of formula 1, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, triethyl citrate, and talc in a solvent (i.e., isopropanol and ethanol). Pellets of the compound of formula 1 were prepared by spraying the coating solution prepared above onto white sugar spheres using a fluid bed granulator (GPCG-1, Glatt GmbH, Germany). A mixture in which tartaric acid, hydroxypropyl cellulose, hydroxypropyl methylcellulose, dimethicone and talc are dissolved in ethanol is sprayed onto the pellets of the compound of formula 1 that are prepared for coating. Clopidogrel hydrogen sulfate, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, triethyl citrate, and talc were dissolved in isopropanol to prepare a coating solution, and then the pellets prepared above were further coated with the coating solution, thereby preparing composite pellets comprising clopidogrel and the compound of formula 1.

The coating was performed under the same conditions as shown in example 2-1.

[ Table 4]

Component name	Amount (mg)
		White sugar ball	50.0
Clopidogrel hydrogen sulfate	97.875
		Compounds of formula 1	50.0
Tartaric acid	25.0
		Hydroxypropyl cellulose	22.0
Talc	7.625
		Hydroxypropyl methylcellulose	14.1
Polydimethylsiloxane	0.6
		Citric acid triethyl ester	1.8

Examples 3-5 Single and two layer tablets comprising particles of clopidogrel and the Compound of formula 1

To prepare a dosage form according to the present invention, granules containing clopidogrel were prepared as follows.

[ Table 5]

Clopidogrel bisulfate, microcrystalline cellulose, mannitol and croscarmellose sodium were mixed together according to the components and contents as shown in table 5, and then a binder solution in which hydroxypropylmethylcellulose was dissolved in an acetone/water mixed solution was added to the resultant mixture, thereby performing coating and drying processes for granules. At the end of the drying, size adjustment is performed, and then microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, and sodium stearyl fumarate are mixed together, thereby completing the granulation of clopidogrel.

The clopidogrel particles prepared above and the compound particles of formula 1 prepared in example 1B were compressed and prepared into tablets as follows.

1) Example 3: tablet compression after mixing clopidogrel particles and compound particles of formula 1 together

2) Examples 4 to 5: compressing the tablet into a two-layered tablet by forming clopidogrel particles (first layer) and compound particles of formula 1 (second layer)

Example 6: multilayer tablet comprising clopidogrel particles and particles of compound of formula 1 together

The compositional characteristics of the particles containing clopidogrel are shown in table 6, and the preparation method thereof is performed in the same manner as shown in examples 3 to 5.

[ Table 6]

Component name	Amount (unit: mg)
		Clopidogrel hydrogen sulfate	97.875
Microcrystalline cellulose	112.125
		Croscarmellose sodium	20.0
Hydroxypropyl methylcellulose	15.0
		Colloidal silicon dioxide	5.0
Stearyl fumarate sodium salt	5.0
		Intermediate layer of pharmaceutical additive	50.0-100.0
B of example 1	200.0

Intermediate layers of the clopidogrel particles prepared above, the compound particles of formula 1 prepared in example 1B, and the pharmaceutical additives are compressed and prepared into a multi-layered tablet. For the intermediate layer of the pharmaceutical additive, all conventionally used additives can be used as follows: microcrystalline cellulose, lactose, mannitol, starch, low-substituted hydroxypropylcellulose, and the like, which proved satisfactory as a result of testing the blend compatibility with the two drugs.

Experimental example 1: evaluation test of drug interactions by non-clinical model

To determine the effect of esomeprazole (PPI drug) and the compound of formula 1 on the efficacy of clopidogrel, pharmacokinetic drug interactions were tested in a manner of administering 20mg of clopidogrel and 20mg of esomeprazole, or 50mg of the compound of formula 1, in combination, to beagle dogs, either once or repeatedly (for seven days).

Specifically, clopidogrel was repeatedly administered to ten beagle dogs for seven days, and then esomeprazole and the compound of formula 1 were administered to those beagle dogs under a steady state in combination for seven days, so that blood was collected therefrom on days 5, 8 and 14 for pharmacokinetic analysis before and after the administration.

The results are shown in fig. 1 to 2. Fig. 1 and 2 are graphs showing clopidogrel active metabolite concentrations in blood, which are measured after combined administration of esomeprazole and the compound of formula 1, respectively. It has been shown that the AUC level for repeated administration of a combination of clopidogrel active metabolite with esomeprazole is 85% and that for repeated administration of a combination of clopidogrel active metabolite with compound of formula 1 is 120%. Thus, it has been determined that the risk of drug interactions between clopidogrel and the compound of formula 1 is low.

Experimental example 2: blend compatibility test

In a state in which clopidogrel alone is present and mixed with the compound of formula 1, a blending compatibility test with additives was performed.

The ratio of the additive to the main component was adjusted, and then the content and the change of the related substances were evaluated under accelerated test conditions (40 ℃/RH 75%) for four weeks, so that the results thereof are shown in fig. 3 to 5.

As a result of considering the results shown in fig. 3 to 5 above, it can be seen that if clopidogrel is brought into direct contact with the compound of formula 1 in spite of the selection of an additive capable of ensuring the stability of clopidogrel, the stability of the drug is deteriorated due to the eutectic phenomenon between the two components.

Experimental example 3: pharmacokinetic evaluation of a combination formulation of clopidogrel and the compound of formula 1 on beagle dogs

Pharmacokinetic evaluations were performed on example 1 (capsule containing clopidogrel pellet and compound of formula 1 granule) and example 5 (multilayer tablet containing clopidogrel granule and compound of formula 1 granule), which are different types of complex formulations in the present invention. Plavix Tab. Comparative example 1 and 50mg of Tab Compound of formula 1. Comparative example 2 was used as a comparative example.

Specifically, the test on 12 beagle dogs was organized under the conditions of single dose, fasting, 3 × 3 and crossover design, and the results of evaluating the blood concentrations of the clopidogrel metabolite and the compound of formula 1 in the comparative examples and examples are shown in fig. 6 and 7.

It was shown that the AUC of example 1 was 96% and the AUC of example 5 was 101% based on the AUC of comparative example 1. Accordingly, it has been determined that various dosage forms of a combination pharmaceutical composition comprising clopidogrel and the compound of formula 1 are implemented while solving the problem of the decrease in drug efficacy of clopidogrel, and thus it can be seen that the objects of the present invention are achieved.

Experimental example 4: comparative elution test

The comparative elution test was performed using method II (paddle method) of the elution test method among the general test methods of Korean Pharmacopoeia (KP). Analyzing by HPLC under the condition that the volume of the eluent is 900 mL; the paddle rotation speed was 50 rpm; the temperature is 37 +/-0.5 ℃; and the detection wavelength was 240, 262 nm. In the comparative elution test, Plavix Tab. Comparative example 1 and 50mg of Tab Compound of formula 1. (comparative example 2) was used as a comparative group.

After the start of elution, comparative evaluation was performed at a cumulative elution rate of 60 minutes, and the elution rate at pH 4.0 is shown in fig. 8 and 10, while the elution rate in water is shown in fig. 9 and 11.

Experimental example 5: stability test

The above examples were subjected to one month stability evaluation under accelerated conditions (40 ℃), and the results thereof are shown in table 7. All prepared examples meet the criteria of stability requirements.

[ Table 7]

Experimental example 6: stability test

The above examples 1 and 6 were subjected to stability evaluation for six months under actual storage conditions and met all stability criteria.

[ Table 8]

From the above description, those skilled in the art to which the present invention pertains will appreciate that the present invention can be embodied in other specific forms without changing the technical spirit or essential features of the invention. In this regard, it should be understood that the above-described exemplary embodiments are illustrative in all respects and are not intended to limit the scope of the invention. It should be understood that the scope of the present invention includes all modifications or changes derived from the meaning and scope of the patent claims to be described below and equivalents thereof, rather than the above detailed description.

Industrial applicability

The present invention is characterized by exhibiting effects of preventing and treating gastrointestinal disorders caused by clopidogrel while maintaining the pharmacological effects of clopidogrel, by using clopidogrel in combination with a compound of formula 1, i.e., an acid secretion inhibitor. Thus, it is contemplated that the present invention may be of value in the relevant pharmaceutical industry.