WO2013133620A1 - Pharmaceutical composition comprising clopidogrel and aspirin and process for preparing the same - Google Patents

Pharmaceutical composition comprising clopidogrel and aspirin and process for preparing the same Download PDF

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Publication number
WO2013133620A1
WO2013133620A1 PCT/KR2013/001792 KR2013001792W WO2013133620A1 WO 2013133620 A1 WO2013133620 A1 WO 2013133620A1 KR 2013001792 W KR2013001792 W KR 2013001792W WO 2013133620 A1 WO2013133620 A1 WO 2013133620A1
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Prior art keywords
aspirin
clopidogrel
containing particles
salt
coating
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PCT/KR2013/001792
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French (fr)
Inventor
Woon-Sook NA
Jeong-Hoon WOO
Chang-Keun Hyun
Yoong-Sik Park
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Yuhan Corporation
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Publication of WO2013133620A1 publication Critical patent/WO2013133620A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system having sulfur as a ring hetero atom, e.g. ticlopidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/60—Salicylic acid; Derivatives thereof
    • A61K31/612—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid
    • A61K31/616—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid by carboxylic acids, e.g. acetylsalicylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • A61K9/2081—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets with microcapsules or coated microparticles according to A61K9/50
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
    • A61K9/5047—Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
    • A61K9/5078—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings with drug-free core
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5084—Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs

Definitions

  • the present invention relates to a pharmaceutical composition comprising clopidogrel and aspirin; and a process for preparing the same. More specifically, the present invention relates to a pharmaceutical composition having excellent stability, formulated through separate particle-coatings of clopidogrel and aspirin, so as not to contact each other; and a process for preparing the same.
  • Clopidogrel whose chemical name is methyl (+)-(S)- ⁇ -(o-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-acetate (dextrorotatory optical isomer), has an activity for inhibiting blood clots, thereby preventing ischemic events by vascular diseases such as atherosclerosis and heart attack.
  • Clopidogrel an anti-platelet agent inhibiting blood clots, is useful for preventing and/or treating various vascular diseases such as arteriosclerosis, stroke, myocardial infarction, peripheral arterial obstructive disease, etc.
  • clopidogrel As a salt of clopidogrel, there are known hydrochloride, hydrogen sulfate, hydrobromide, taurocholate, etc.
  • clopidogrel is clinically used in the hydrogen sulfate form, i.e., clopidogrel hydrogen sulfate (C 16 H 16 ClNO 2 S ⁇ H 2 SO 4 ), which is also referred to "clopidogrel bisulfate”.
  • clopidogrel or its salt has very inferior physicochemical properties, which makes it difficult to formulate into pharmaceutical compositions.
  • Contact between clopidogrel or its salt and an aqueous solution results in aggregation and/or gelation, which leads to delaying disintegration.
  • clopidogrel or its salt is very hygroscopic and easily hydrolyzed under the presence of water, it has very low stability.
  • clopidogrel or its salt exhibits an interaction with conventionally used pharmaceutical excipients, which also brings about stability problems.
  • conventionally used pharmaceutical excipients which also brings about stability problems.
  • alkali metal e.g., Na
  • alkali earth metal e.g., Ca, Ma
  • magnesium stearate for example, magnesium stearate, etc.
  • the high surface static electricity of clopidogrel or its salt also causes sticking to the punches during the manufacture of tablets, which makes it difficult to perform industrial mass production.
  • the present inventors have disclosed stabilized clopidogrel-containing particles obtained by coating clopidogrel or its salt with hydroxypropyl cellulose or hydroxypropyl methylcellulose, a process for the preparation thereof, and a pharmaceutical composition comprising the same (Korean Patent No. 10-0809903).
  • aspirin known as acetylsalicylic acid
  • aspirin is used as an analgesic to relieve fever and pains.
  • aspirin is also used for reducing non-fatal myocardial infarction risk and ischemic attack risk in patients with unstable angina, through the inhibition of platelet aggregation, and for preventing re-infarction after a first myocardial infarction.
  • International Publication No. WO97/029753 disclosed that the combination of clopidogrel and aspirin is expected to exhibit a synergistic effect.
  • WO2009/104932 disclosed a combination formulation e.g., in a triple-layered tablet form, which comprises a prior-release compartment comprising aspirin or its salt; and a delayed-release compartment comprising clopidogrel or its salt, and a placebo layer which does not contain an active ingredient.
  • the combination formulation is designed for controlling drug-release profiles in such a manner that aspirin is allowed to work first and then clopidogrel is allowed to work.
  • the resulting combination formulation did not only exhibit equal or greater dissolution rate compared with each single formulation but also minimize content changes and impurity formations, thereby accomplishing excellent stability.
  • a pharmaceutical composition comprising (a) aspirin-containing particles having a coating layer formed on aspirin or its salt, wherein the coating layer comprises a copolymer of methacrylic acid and ethyl acrylate in a weight ratio of 1:1 or hydroxypropyl cellulose phthalate; and (b) clopidogrel-containing particles having a coating layer formed on clopidogrel or its salt, wherein the coating layer comprises hydroxypropyl cellulose or hydroxypropyl methylcellulose.
  • the copolymer of methacrylic acid and ethyl acrylate in a weight ratio of 1:1 or hydroxypropyl cellulose phthalate may be present in an amount ranging from 10 to 40 parts by weight, based on 100 parts by weight of aspirin or its salt.
  • the hydroxypropyl cellulose or hydroxypropyl methylcellulose may be present in an amount ranging from 5 to 40 parts by weight, based on 100 parts by weight of clopidogrel or its salt.
  • the aspirin-containing particles and/or the clopidogrel-containing particles may be in a powder form, in a granule form, in a pellet form, or in a mini tablet form.
  • the clopidogrel-containing particles may be in a mini tablet form.
  • the pharmaceutical composition of the present invention may be in a dosage form of capsule, tablet, or granule.
  • a process for preparing a pharmaceutical composition comprising: (i) coating aspirin or its salt with a coating solution to obtain aspirin-containing particles, wherein the coating solution comprises a copolymer of methacrylic acid and ethyl acrylate in a weight ratio of 1:1 or hydroxypropyl cellulose phthalate; (ii) coating clopidogrel or its salt with a coating solution to obtain clopidogrel-containing particles, wherein the coating solution comprises hydroxypropyl cellulose or hydroxypropyl methylcellulose; and (iii) forming capsules, tablets, or granules using the aspirin-containing particles obtained in the step (i), the clopidogrel-containing particles obtained in the step (ii), and optionally a pharmaceutically acceptable excipient.
  • a process for preparing a capsule formulation comprising: (i) coating aspirin or its salt with a coating solution to obtain aspirin-containing particles, wherein the coating solution comprises a copolymer of methacrylic acid and ethyl acrylate in a weight ratio of 1:1 or hydroxypropyl cellulose phthalate; (ii') coating clopidogrel or its salt with a coating solution to obtain clopidogrel-containing particles, wherein the coating solution comprises hydroxypropyl cellulose or hydroxypropyl methylcellulose, and then compressing the clopidogrel-containing particles and a pharmaceutically acceptable excipient to obtain clopidogrel-containing tablets; and (iii') filling a capsule with the aspirin-containing particles obtained in the step (i) and the clopidogrel-containing tablets obtained in the step (ii').
  • the pharmaceutical composition according to the present invention is a combination formulation in a single dosage form which is formulated through separate particle-coatings of clopidogrel or its salt and aspirin or its salt with a specific polymer, so as not to contact each other. Therefore, the pharmaceutical composition according to the present invention can minimize content changes and impurity formations, thereby accomplishing excellent stability. Especially, the pharmaceutical composition of the present invention can remarkably reduce the formation of degradation products of aspirin according to long-term storage. In addition, the pharmaceutical composition of the present invention exhibits equal or greater dissolution rate and bioavailability compared with each single formulation, thereby being able to minimize potential interference in each drug release.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising (a) aspirin-containing particles having a coating layer formed on aspirin or its salt, wherein the coating layer comprises a copolymer of methacrylic acid and ethyl acrylate in a weight ratio of 1:1 or hydroxypropyl cellulose phthalate; and (b) clopidogrel-containing particles having a coating layer formed on clopidogrel or its salt, wherein the coating layer comprises hydroxypropyl cellulose or hydroxypropyl methylcellulose.
  • the aspirin-containing particles may be obtained by coating aspirin or its salt with a specific enteric polymer, i.e., a copolymer of methacrylic acid and ethyl acrylate in a weight ratio of 1:1 [for example, Eudragit L30D55 TM (Evonic), etc.] or hydroxypropyl cellulose phthalate.
  • a specific enteric polymer i.e., a copolymer of methacrylic acid and ethyl acrylate in a weight ratio of 1:1 [for example, Eudragit L30D55 TM (Evonic), etc.] or hydroxypropyl cellulose phthalate.
  • the coating i.e., particle-coating according to the present invention, may be performed using aspirin or its salt per se (i.e., synthetic law material per se ), using aspirin or its salt in a granular form (hereinafter, also referred to as 'aspirin granules'), or using aspirin or its salt in a pellet form which may be obtained by coating an inert core with aspirin or its salt (hereinafter, also referred to as 'aspirin pellets').
  • the aspirin granules and/or aspirin pellets have better physicochemical properties such as appearance, flowability, etc., thereby being able to perform the particle-coating more efficiently.
  • the aspirin granules may be obtained by conventional wet or dry granulation methods.
  • commercially available aspirin granules for example Rhodine 2316 TM (Rhodia) may be also used in the present invention.
  • the aspirin pellets may be obtained by coating a commercially available inert core, for example, Sugar spheres, with aspirin. The coating may be performed using povidone, hydroxypropyl cellulose, or hydroxypropyl methylcellulose as a binder.
  • the copolymer of methacrylic acid and ethyl acrylate in a weight ratio of 1:1 or hydroxypropyl cellulose phthalate may be present in an amount ranging from 10 to 40 parts by weight, preferably from 15 to 30 parts by weight, based on 100 parts by weight of aspirin or its salt. When the amount thereof is below 10 parts by weight, stability of the resulting formulation may become lowered. And also, when the amount thereof is above 40 parts by weight, dissolution rate of aspirin may become lowered.
  • the aspirin-containing particles may further comprise a plasticizer (for example, triethyl citrate); and a lubricant (for example, talc), in addition to said coating agent.
  • the aspirin-containing particles may be obtained by performing the particle-coating with a coating solution comprising triethyl citrate and/or talc, in addition to a copolymer of methacrylic acid and ethyl acrylate in a weight ratio of 1:1 or hydroxypropyl cellulose phthalate.
  • the clopidogrel-containing particles may be prepared according to our previous Korean patent No. 10-0809903. That is, the clopidogrel-containing particles may be obtained by coating clopidogrel or its salt with hydroxypropyl cellulose or hydroxypropyl methylcellulose.
  • the hydroxypropyl cellulose or hydroxypropyl methylcellulose may be present in an amount ranging from 5 to 40 parts by weight, preferably from 10 to 30 parts by weight, based on 100 parts by weight of clopidogrel or its salt. When the amount thereof is below 5 parts by weight, shield effect and/or improvement of surface properties may become insufficient. And also, when the amount thereof is above 40 parts by weight, dissolution rate of clopidogrel may become lowered.
  • the clopidogrel-containing particles may further comprise a glidant (for example, silicon dioxide), a plasticizer (for example, polyethylene glycol), etc.
  • the aspirin-containing particles and/or the clopidogrel-containing particles may be in a powder form, in a granule form, in a pellet form, or in a mini tablet form.
  • the clopidogrel-containing particles may be in a mini tablet form (for example, mini tablets having 2 to 6 mm of diameter).
  • the clopidogrel-containing particles and the aspirin-containing particles may be formulated into a dosage form of capsule, tablet, or granule.
  • a capsule formulation may be obtained by preparing tablets (for example, mini tablets having 2 to 6 mm of diameter) from the clopidogrel-containing particles, optionally using a pharmaceutically acceptable excipient; and then filling a capsule with the obtained tablets and the aspirin-containing particles.
  • the pharmaceutical composition of the present invention may be in a solid dosage form for oral administration, preferably a dosage form of capsule, tablet, or granule.
  • the dosage form of capsule, tablet, or granule may further comprise a pharmaceutically acceptable excipient, for example, a diluent, a binder, a lubricant, etc.
  • a pharmaceutically acceptable excipient for example, a diluent, a binder, a lubricant, etc.
  • the diluent include microcrystalline cellulose (for example, Ceolus TM ), starch, pregelatinized starch, lactose, etc.
  • the binder include hydroxypropyl cellulose, etc.
  • the lubricant include talc, zinc stearate, magnesium stearate, Aerosil 200, etc.
  • the present invention includes, within its scope, a process for preparing said pharmaceutical composition. That is, the present invention includes a process for preparing a pharmaceutical composition, the process of which comprises: (i) coating aspirin or its salt with a coating solution to obtain aspirin-containing particles, wherein the coating solution comprises a copolymer of methacrylic acid and ethyl acrylate in a weight ratio of 1:1 or hydroxypropyl cellulose phthalate; (ii) coating clopidogrel or its salt with a coating solution to obtain clopidogrel-containing particles, wherein the coating solution comprises hydroxypropyl cellulose or hydroxypropyl methylcellulose; and (iii) forming capsules, tablets, or granules using the aspirin-containing particles obtained in the step (i), the clopidogrel-containing particles obtained in the step (ii), and optionally a pharmaceutically acceptable excipient.
  • the step (i) and (ii) may be carried out changing the order or simultaneously. That is, the step (i) and (ii) may be carried out independently.
  • the coatings of step (i) and (ii) may be performed according to conventional coating methods in the field of pharmaceutics, for example according to a fluid bed coating method.
  • the forming capsules, tablets, or granules of step (iii) may be also performed according to conventional formulation methods in the field of pharmaceutics.
  • a capsule formulation may be prepared by filing a capsule with the aspirin-containing particles obtained in the step (i), the clopidogrel-containing particles obtained in the step (ii), and optionally a pharmaceutically acceptable excipient, according to a conventional filling method.
  • the tablet formulation may be prepared by compressing a mixture of the aspirin-containing particles obtained in the step (i), the clopidogrel-containing particles obtained in the step (ii), and optionally a pharmaceutically acceptable excipient. If necessary, an additional coating (for example, film coating) may be performed. And also, the tablet formulation may be in a bi-layer tablet form, which may be prepared using a multi-layer tablet compressor. If necessary, the tablet formulation may be in a triple or more multi-layer tablet form to which e.g., a placebo layer is further added. If necessary, an additional coating (for example, film coating) may be performed on the resulting multi-layer tablet (e.g., bi-layer or triple-layer tablet).
  • an additional coating for example, film coating
  • the present invention also provides a process for preparing a capsule formulation, the process of which comprises: (i) coating aspirin or its salt with a coating solution to obtain aspirin-containing particles, wherein the coating solution comprises a copolymer of methacrylic acid and ethyl acrylate in a weight ratio of 1:1 or hydroxypropyl cellulose phthalate; (ii') coating clopidogrel or its salt with a coating solution to obtain clopidogrel-containing particles, wherein the coating solution comprises hydroxypropyl cellulose or hydroxypropyl methylcellulose, and then compressing the clopidogrel-containing particles and a pharmaceutically acceptable excipient to obtain clopidogrel-containing tablets; and (iii') filling a capsule with the aspirin-containing particles obtained in the step (i) and the clopidogrel-containing tablets obtained in the step (ii').
  • the step (i) and (ii') may be carried out changing the order or simultaneously. That is, the step (i) and (ii') may be carried out independently.
  • the coatings of step (i) and (ii') may be performed according to conventional coating methods in the field of pharmaceutics, for example according to a fluid bed coating process. If necessary, an additional coating (for example, film coating) may be performed on the clopidogrel-containing tablets obtained in the step (ii').
  • the filling of step (iii') may be also performed according to conventional filling methods in the field of pharmaceutics.
  • Aspirin-containing particles were prepared according to the components and amounts shown in Table 1.
  • the aspirin granules used in Table 1 were Rhodine 2316 TM (Rhodia).
  • the used aspirin granules (1,111.1 g) correspond to 1,000.0 g of aspirin.
  • Eudragit L30D55 TM (Evonic), triethyl citrate, and talc were dissolved and dispersed in water to obtain a coating solution.
  • the aspirin granules were coated with the coating solution, using a fluid bed granulator [GPCG-1 (GLATT, Germany)], under the following conditions: 40 ⁇ 60 °C of inlet temperature, 25 ⁇ 35°C of outlet temperature, 25 ⁇ 35°C of product temperature, 2 ⁇ 5 mL/min of spray rate.
  • GPCG-1 fluid bed granulator
  • Aspirin-containing particles were prepared according to the components and amounts shown in Table 2.
  • the aspirin granules used in Table 2 were Rhodine 2316 TM (Rhodia).
  • the used aspirin granules (1,111.1 g) correspond to 1,000.0 g of aspirin.
  • Hydroxypropyl cellulose phthalate, triethyl citrate, and talc were dissolved and dispersed in a mixed solvent of ethanol and acetone (1:1) to obtain a coating solution.
  • the aspirin granules were coated with the coating solution, using a fluid bed granulator [GPCG-1 (GLATT, Germany)], under the same conditions as in Example 1.
  • Aspirin pellets were prepared according to the components and amounts shown in Table 3. Hydroxypropyl cellulose and aspirin were dissolved and dispersed in ethanol to obtain a coating solution. An inert core (Sugar spheres) was coated with the coating solution, using a fluid bed granulator [GPCG-1 (GLATT, Germany)] to obtain aspirin pellets. The coating conditions were as followings: 45 ⁇ 60°C of inlet temperature, 25 ⁇ 35°C of outlet temperature, 25 ⁇ 35°C of product temperature, 8 mL/min of spray rate.
  • Aspirin-containing particles were prepared according to the components and amounts shown in Table 4. Hydroxypropyl cellulose phthalate, triethyl citrate, and talc were dissolved and dispersed in a mixed solvent of ethanol and acetone (1:1) to obtain a coating solution. The aspirin pellets were coated with the coating solution, using a fluid bed granulator [GPCG-1 (GLATT, Germany)], under the same conditions as in Example 1.
  • GPCG-1 GLATT, Germany
  • Clopidogrel-containing particles in a granule form were prepared according to the components and amounts shown in Table 5 and Table 6.
  • the used clopidogrel hydrogen sulfate (978.75 g) corresponds to 750 g of clopidogrel.
  • Hydroxypropyl methylcellulose (Pharmacoat 603 TM , Shinetsu) was dispersed in a mixed solvent of ethanol and methylene chloride (1:1) to obtain a coating solution.
  • the clopidogrel hydrogen sulfate was coated with the coating solution, using a fluid bed granulator [GPCG-1 (GLATT, Germany)], under the following conditions: 60 ⁇ 70°C of inlet temperature, 35 ⁇ 45°C of outlet temperature, 35 ⁇ 45°C of product temperature, 5 mL/min of spray rate.
  • GPCG-1 fluid bed granulator
  • Clopidogrel-containing mini tablets were prepared according to the components and amounts shown in Table 7.
  • the amounts of the table 7 refer to the amounts (in mg) per 1 mini tablet.
  • a mixture of clopidogrel-containing particles (the particles obtained in Example 4-3), microcrystalline cellulose, and L-hydroxypropyl cellulose (L-HPC) was mixed with a mixture of Aerosil 200 and sodium stearyl fumarate. The resulting mixture was compressed to obtain mini tablets (diameter: 6 mm).
  • the tablets of Example 6-2 and 6-3 were further film-coated. That is, hydroxypropyl methylcellulose, polyethylene glycol 6000, titanium dioxide, and iron oxide were dispersed in water to obtain a coating solution, with which the mini tablets were coated.
  • Example 4-3 109.6 109.6 109.6 Excipient Microcrystalline cellulose 52.4 52.4 52.4 L-Hydroxypropyl cellulose 12.0 12.0 12.0 Aerosil 200 3.0 3.0 3.0 Sodium stearyl fumarate 3.0 3.0 3.0 Coating material Hydroxypropyl methylcellulose 8.0 16.0 Polyethylene glycol 6000 1.0 2.0 Titanium dioxide 0.9 1.8 Iron oxide 0.1 0.2 Total 180 190 200
  • Capsules were prepared according to the components and amounts shown in Table 8 and Table 9. The amounts of the tables 8 and 9 refer to the amounts (in mg) per 1 capsule.
  • Clopidogrel-containing particles were mixed with talc (and microcrystalline cellulose in case of Example 7-7) to obtain a mixture (mixture A).
  • Aspirin-containing particles were mixed with talc to obtain a mixture (mixture B).
  • the mixture A was filled in a # 1 capsule and then the mixture B was filled therein to prepare capsules.
  • Capsules were prepared according to the components and amounts shown in Table 10.
  • the amounts of the table 10 refer to the amounts (in mg) per 1 capsule.
  • the clopidogrel-containing tablets were manually filled in a # 1 capsule and then the aspirin-containing particles were filled therein to prepare capsules.
  • Tablets were prepared according to the components and amounts shown in Table 11.
  • the amounts of the table 11 refer to the amounts (in mg) per 1 mini tablet.
  • a mixture of clopidogrel-containing particles, aspirin-containing particles, microcrystalline cellulose, starch 1500, and L-hydroxypropyl cellulose (L-HPC) was mixed with a mixture of Aerosil 200 and stearic acid. The resulting mixture was compressed to obtain tablets.
  • Aspirin-containing particles Example 1-4 146.67 146.67
  • Excipient Microcrystalline cellulose 114.73 114.73 113.63 113.63 Starch 1500 77 77 77 77 L-HPC 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 Aerosil 200 6 6 6 6 6 6 6 Stearic acid 6 6 6 6 6 Total 480
  • Capsules were prepared in the same procedures as in Examples 7 and 8, according to the components and amounts shown in Table 12.
  • the aspirin granules (111.11 mg) correspond to 100 mg of aspirin; and the clopidogrel hydrogen sulfate (97.875 mg) corresponds to 75 mg of clopidogrel.
  • the capsule i.e., the capsule of Comparative Example 3
  • the capsule prepared from the clopidogrel-containing particles, in which hydroxypropyl methylcellulose was coated in amount of more than 40 parts by weight, based on 100 parts by weight of clopidogrel hydrogen sulfate, showed remarkably reduced dissolution rate.
  • the capsules filled with the mini tablet obtained from the clopidogrel-containing particles; and the tablets prepared by compressing the clopidogrel-containing particles also showed good dissolution rate, i.e., more than 80% of dissolution rate, which is a US Pharmacopeia (USP) standard.
  • USP US Pharmacopeia
  • the dissolution tests of the capsules prepared in Examples 8-1 to 8-8, 9-1, 9-3, 10-1, 10-3, and Comparative Examples 1, 4, 5 were performed. Specifically, initial dissolution tests of the respective capsules were performed in a pH 1.0 buffer for 2 hours; and then the consecutive dissolution tests of the respective remaining formulations were performed in a pH 6.8 buffer (obtained by adding a 0.2M sodium phosphate tribasic solution to each dissolution medium) for 90 minutes. The dissolution rates (%) are presented in the following tables 15 and 16.
  • the capsules prepared according to the present invention showed low dissolution rate, i.e., less than 10% of dissolution rate in a pH 1.0 buffer and high dissolution rate in a pH 6.8 buffer.
  • the capsule prepared from non-coated aspirin i.e., the capsule of Comparative Example 1
  • most of aspirin was dissolved in a pH 1.0 buffer.
  • the capsule prepared from the aspirin-containing particles having the coating agent in an amount of less than 10 parts by weights based on 100 parts by weight of aspirin granule i.e., the capsule of Comparative Example 4
  • more than 10% of aspirin was dissolved in a gastric acid condition.
  • the capsule prepared from the aspirin-containing particles having the coating agent in an amount of more than 40 parts by weights based on 100 parts by weight of aspirin granule i.e., the capsule of Comparative Example 5
  • showed poor dissolution rate in a pH 6.8 buffer i.e., less than 80% of dissolution rate, although aspirin was not dissolved in a gastric acid condition significantly.
  • the capsules containing the aspirin-containing particles obtained from the aspirin pellets; and the tablets prepared by compressing the aspirin-containing particles showed low dissolution rate, i.e., less than 10% of dissolution rate in a pH 1.0 buffer; and good dissolution rate, i.e., more than 80% of dissolution rate in a pH 6.8 buffer, which is a US Pharmacopeia (USP) standard.
  • USP US Pharmacopeia
  • Stabilities of the capsules prepared in Examples 7-2, 7-6, 8-3, 8-7 and Comparative Examples 1, 2, 4, 6 were evaluated under accelerated conditions (40 °C, a relative humidity of 75 %) for 1 month.
  • the stability test results are shown in Table 17 (contents, %) and Table 18 (impurities, %).
  • the impurities A and C represent the degradation products originated from clopidogrel; and salicylic acid represents the degradation product of aspirin.
  • the capsule prepared from the aspirin-containing particles having less than 5 parts by weight of the coating agent based on 100 parts by weight of aspirin granules i.e., the capsule of Comparative Example 4
  • the amount of salicylic acid was remarkably increased.
  • the capsules prepared according to the present invention i.e., the capsules of Example 7-2, 7-6, 8-3, and 8-7

Abstract

The present invention provides a pharmaceutical composition comprising (a) aspirin-containing particles having a coating layer formed on aspirin or its salt, wherein the coating layer comprises a copolymer of methacrylic acid and ethyl acrylate in a weight ratio of 1:1 or hydroxypropyl cellulose phthalate; and (b) clopidogrel-containing particles having a coating layer formed on clopidogrel or its salt, wherein the coating layer comprises hydroxypropyl cellulose or hydroxypropyl methylcellulose. And also, the present invention provides a process for preparing the pharmaceutical composition.

Description

PHARMACEUTICAL COMPOSITION COMPRISING CLOPIDOGREL AND ASPIRIN AND PROCESS FOR PREPARING THE SAME
The present invention relates to a pharmaceutical composition comprising clopidogrel and aspirin; and a process for preparing the same. More specifically, the present invention relates to a pharmaceutical composition having excellent stability, formulated through separate particle-coatings of clopidogrel and aspirin, so as not to contact each other; and a process for preparing the same.
Clopidogrel, whose chemical name is methyl (+)-(S)-α-(o-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-acetate (dextrorotatory optical isomer), has an activity for inhibiting blood clots, thereby preventing ischemic events by vascular diseases such as atherosclerosis and heart attack. Clopidogrel, an anti-platelet agent inhibiting blood clots, is useful for preventing and/or treating various vascular diseases such as arteriosclerosis, stroke, myocardial infarction, peripheral arterial obstructive disease, etc. As a salt of clopidogrel, there are known hydrochloride, hydrogen sulfate, hydrobromide, taurocholate, etc. Currently, clopidogrel is clinically used in the hydrogen sulfate form, i.e., clopidogrel hydrogen sulfate (C16H16ClNO2S·H2SO4), which is also referred to "clopidogrel bisulfate".
However, clopidogrel or its salt has very inferior physicochemical properties, which makes it difficult to formulate into pharmaceutical compositions. Contact between clopidogrel or its salt and an aqueous solution results in aggregation and/or gelation, which leads to delaying disintegration. Especially, since clopidogrel or its salt is very hygroscopic and easily hydrolyzed under the presence of water, it has very low stability. For example, when clopidogrel hydrogen sulfate is placed under the conditions of 65 ℃ / 75 % relative humidity, the amounts of degradation products, i.e., impurity A ((+)-(S)-(o-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetic acid) and impurity C (methyl (-)-(R)-o-chlorophenyl-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate, hydrogen sulfate) are significantly increased in a time-dependent manner. And also, clopidogrel or its salt, including clopidogrel hydrogen sulfate, exhibits an interaction with conventionally used pharmaceutical excipients, which also brings about stability problems. For example, there are undesirable interactions between clopidogrel hydrogen sulfate and excipients containing alkali metal (e.g., Na) and/or alkali earth metal (e.g., Ca, Ma) [for example, magnesium stearate, etc.] (see US Patent Publication No. 2003/0096837). In addition, the high surface static electricity of clopidogrel or its salt also causes sticking to the punches during the manufacture of tablets, which makes it difficult to perform industrial mass production. In order to improve these inferior properties in formulating into pharmaceutical compositions, i.e., poor stability due to hydrolysis, interaction with excipients, and tableting problems such as sticking, the present inventors have disclosed stabilized clopidogrel-containing particles obtained by coating clopidogrel or its salt with hydroxypropyl cellulose or hydroxypropyl methylcellulose, a process for the preparation thereof, and a pharmaceutical composition comprising the same (Korean Patent No. 10-0809903).
Meanwhile, aspirin, known as acetylsalicylic acid, is used as an analgesic to relieve fever and pains. Recently, aspirin is also used for reducing non-fatal myocardial infarction risk and ischemic attack risk in patients with unstable angina, through the inhibition of platelet aggregation, and for preventing re-infarction after a first myocardial infarction. International Publication No. WO97/029753 disclosed that the combination of clopidogrel and aspirin is expected to exhibit a synergistic effect. And also, International Publication No. WO2009/104932 disclosed a combination formulation e.g., in a triple-layered tablet form, which comprises a prior-release compartment comprising aspirin or its salt; and a delayed-release compartment comprising clopidogrel or its salt, and a placebo layer which does not contain an active ingredient. The combination formulation is designed for controlling drug-release profiles in such a manner that aspirin is allowed to work first and then clopidogrel is allowed to work.
During the development of a combination formulation in a single dosage form containing clopidogrel and aspirin as active ingredients, the present inventors found that the contact between clopidogrel and aspirin brings about significant changes in their contents and increased formation of degradation products. In order to address these problems, the present inventors designed various formulations having a single dosage form in which clopidogrel and aspirin could not contact each other; and then evaluated pharmaceutical properties, such as stability thereof and interference in each drug release. As a result, the present inventors found that, when preparing clopidogrel-containing particles through particle-coating according to our previous Korean patent No. 10-0809903 and aspirin-containing particles through particle-coating with a certain polymer, respectively; and then formulating the clopidogrel-containing particles and the aspirin-containing particles into a single dosage form, the resulting combination formulation did not only exhibit equal or greater dissolution rate compared with each single formulation but also minimize content changes and impurity formations, thereby accomplishing excellent stability.
Therefore, it is an object of the present invention to provide a combination formulation in a single dosage form having excellent stability, formulated through separate particle-coatings of clopidogrel and aspirin so as not to contact each other.
It is another object of the present invention to provide a process for preparing the combination formulation.
In accordance with an aspect of the present invention, there is provided a pharmaceutical composition comprising (a) aspirin-containing particles having a coating layer formed on aspirin or its salt, wherein the coating layer comprises a copolymer of methacrylic acid and ethyl acrylate in a weight ratio of 1:1 or hydroxypropyl cellulose phthalate; and (b) clopidogrel-containing particles having a coating layer formed on clopidogrel or its salt, wherein the coating layer comprises hydroxypropyl cellulose or hydroxypropyl methylcellulose.
In the pharmaceutical composition of the present invention, the copolymer of methacrylic acid and ethyl acrylate in a weight ratio of 1:1 or hydroxypropyl cellulose phthalate may be present in an amount ranging from 10 to 40 parts by weight, based on 100 parts by weight of aspirin or its salt. And also, the hydroxypropyl cellulose or hydroxypropyl methylcellulose may be present in an amount ranging from 5 to 40 parts by weight, based on 100 parts by weight of clopidogrel or its salt.
In the pharmaceutical composition of the present invention, the aspirin-containing particles and/or the clopidogrel-containing particles may be in a powder form, in a granule form, in a pellet form, or in a mini tablet form. In an embodiment, the clopidogrel-containing particles may be in a mini tablet form.
And also, in an embodiment, the pharmaceutical composition of the present invention may be in a dosage form of capsule, tablet, or granule.
In accordance with another aspect of the present invention, there is provided a process for preparing a pharmaceutical composition, the process of which comprises: (i) coating aspirin or its salt with a coating solution to obtain aspirin-containing particles, wherein the coating solution comprises a copolymer of methacrylic acid and ethyl acrylate in a weight ratio of 1:1 or hydroxypropyl cellulose phthalate; (ii) coating clopidogrel or its salt with a coating solution to obtain clopidogrel-containing particles, wherein the coating solution comprises hydroxypropyl cellulose or hydroxypropyl methylcellulose; and (iii) forming capsules, tablets, or granules using the aspirin-containing particles obtained in the step (i), the clopidogrel-containing particles obtained in the step (ii), and optionally a pharmaceutically acceptable excipient.
In accordance with still another aspect of the present invention, there is provided a process for preparing a capsule formulation, the process of which comprises: (i) coating aspirin or its salt with a coating solution to obtain aspirin-containing particles, wherein the coating solution comprises a copolymer of methacrylic acid and ethyl acrylate in a weight ratio of 1:1 or hydroxypropyl cellulose phthalate; (ii') coating clopidogrel or its salt with a coating solution to obtain clopidogrel-containing particles, wherein the coating solution comprises hydroxypropyl cellulose or hydroxypropyl methylcellulose, and then compressing the clopidogrel-containing particles and a pharmaceutically acceptable excipient to obtain clopidogrel-containing tablets; and (iii') filling a capsule with the aspirin-containing particles obtained in the step (i) and the clopidogrel-containing tablets obtained in the step (ii').
The pharmaceutical composition according to the present invention is a combination formulation in a single dosage form which is formulated through separate particle-coatings of clopidogrel or its salt and aspirin or its salt with a specific polymer, so as not to contact each other. Therefore, the pharmaceutical composition according to the present invention can minimize content changes and impurity formations, thereby accomplishing excellent stability. Especially, the pharmaceutical composition of the present invention can remarkably reduce the formation of degradation products of aspirin according to long-term storage. In addition, the pharmaceutical composition of the present invention exhibits equal or greater dissolution rate and bioavailability compared with each single formulation, thereby being able to minimize potential interference in each drug release.
The present invention provides a pharmaceutical composition comprising (a) aspirin-containing particles having a coating layer formed on aspirin or its salt, wherein the coating layer comprises a copolymer of methacrylic acid and ethyl acrylate in a weight ratio of 1:1 or hydroxypropyl cellulose phthalate; and (b) clopidogrel-containing particles having a coating layer formed on clopidogrel or its salt, wherein the coating layer comprises hydroxypropyl cellulose or hydroxypropyl methylcellulose.
The aspirin-containing particles may be obtained by coating aspirin or its salt with a specific enteric polymer, i.e., a copolymer of methacrylic acid and ethyl acrylate in a weight ratio of 1:1 [for example, Eudragit L30D55TM (Evonic), etc.] or hydroxypropyl cellulose phthalate.
The coating, i.e., particle-coating according to the present invention, may be performed using aspirin or its salt per se (i.e., synthetic law material per se), using aspirin or its salt in a granular form (hereinafter, also referred to as 'aspirin granules'), or using aspirin or its salt in a pellet form which may be obtained by coating an inert core with aspirin or its salt (hereinafter, also referred to as 'aspirin pellets'). The aspirin granules and/or aspirin pellets have better physicochemical properties such as appearance, flowability, etc., thereby being able to perform the particle-coating more efficiently. The aspirin granules may be obtained by conventional wet or dry granulation methods. In addition, commercially available aspirin granules, for example Rhodine 2316TM (Rhodia), may be also used in the present invention. The aspirin pellets may be obtained by coating a commercially available inert core, for example, Sugar spheres, with aspirin. The coating may be performed using povidone, hydroxypropyl cellulose, or hydroxypropyl methylcellulose as a binder.
The copolymer of methacrylic acid and ethyl acrylate in a weight ratio of 1:1 or hydroxypropyl cellulose phthalate may be present in an amount ranging from 10 to 40 parts by weight, preferably from 15 to 30 parts by weight, based on 100 parts by weight of aspirin or its salt. When the amount thereof is below 10 parts by weight, stability of the resulting formulation may become lowered. And also, when the amount thereof is above 40 parts by weight, dissolution rate of aspirin may become lowered. The aspirin-containing particles may further comprise a plasticizer (for example, triethyl citrate); and a lubricant (for example, talc), in addition to said coating agent. Therefore, the aspirin-containing particles may be obtained by performing the particle-coating with a coating solution comprising triethyl citrate and/or talc, in addition to a copolymer of methacrylic acid and ethyl acrylate in a weight ratio of 1:1 or hydroxypropyl cellulose phthalate.
The clopidogrel-containing particles may be prepared according to our previous Korean patent No. 10-0809903. That is, the clopidogrel-containing particles may be obtained by coating clopidogrel or its salt with hydroxypropyl cellulose or hydroxypropyl methylcellulose. The hydroxypropyl cellulose or hydroxypropyl methylcellulose may be present in an amount ranging from 5 to 40 parts by weight, preferably from 10 to 30 parts by weight, based on 100 parts by weight of clopidogrel or its salt. When the amount thereof is below 5 parts by weight, shield effect and/or improvement of surface properties may become insufficient. And also, when the amount thereof is above 40 parts by weight, dissolution rate of clopidogrel may become lowered. If necessary, the clopidogrel-containing particles may further comprise a glidant (for example, silicon dioxide), a plasticizer (for example, polyethylene glycol), etc.
In the pharmaceutical composition of the present invention, the aspirin-containing particles and/or the clopidogrel-containing particles may be in a powder form, in a granule form, in a pellet form, or in a mini tablet form. In an embodiment, the clopidogrel-containing particles may be in a mini tablet form (for example, mini tablets having 2 to 6 mm of diameter).
The clopidogrel-containing particles and the aspirin-containing particles, optionally along with a pharmaceutically acceptable excipient, may be formulated into a dosage form of capsule, tablet, or granule. And also, a capsule formulation may be obtained by preparing tablets (for example, mini tablets having 2 to 6 mm of diameter) from the clopidogrel-containing particles, optionally using a pharmaceutically acceptable excipient; and then filling a capsule with the obtained tablets and the aspirin-containing particles.
The pharmaceutical composition of the present invention may be in a solid dosage form for oral administration, preferably a dosage form of capsule, tablet, or granule. The dosage form of capsule, tablet, or granule may further comprise a pharmaceutically acceptable excipient, for example, a diluent, a binder, a lubricant, etc. Examples of the diluent include microcrystalline cellulose (for example, CeolusTM), starch, pregelatinized starch, lactose, etc. Examples of the binder include hydroxypropyl cellulose, etc. Examples of the lubricant include talc, zinc stearate, magnesium stearate, Aerosil 200, etc.
The present invention includes, within its scope, a process for preparing said pharmaceutical composition. That is, the present invention includes a process for preparing a pharmaceutical composition, the process of which comprises: (i) coating aspirin or its salt with a coating solution to obtain aspirin-containing particles, wherein the coating solution comprises a copolymer of methacrylic acid and ethyl acrylate in a weight ratio of 1:1 or hydroxypropyl cellulose phthalate; (ii) coating clopidogrel or its salt with a coating solution to obtain clopidogrel-containing particles, wherein the coating solution comprises hydroxypropyl cellulose or hydroxypropyl methylcellulose; and (iii) forming capsules, tablets, or granules using the aspirin-containing particles obtained in the step (i), the clopidogrel-containing particles obtained in the step (ii), and optionally a pharmaceutically acceptable excipient.
The step (i) and (ii) may be carried out changing the order or simultaneously. That is, the step (i) and (ii) may be carried out independently. The coatings of step (i) and (ii) may be performed according to conventional coating methods in the field of pharmaceutics, for example according to a fluid bed coating method. The forming capsules, tablets, or granules of step (iii) may be also performed according to conventional formulation methods in the field of pharmaceutics. For example, a capsule formulation may be prepared by filing a capsule with the aspirin-containing particles obtained in the step (i), the clopidogrel-containing particles obtained in the step (ii), and optionally a pharmaceutically acceptable excipient, according to a conventional filling method. The tablet formulation may be prepared by compressing a mixture of the aspirin-containing particles obtained in the step (i), the clopidogrel-containing particles obtained in the step (ii), and optionally a pharmaceutically acceptable excipient. If necessary, an additional coating (for example, film coating) may be performed. And also, the tablet formulation may be in a bi-layer tablet form, which may be prepared using a multi-layer tablet compressor. If necessary, the tablet formulation may be in a triple or more multi-layer tablet form to which e.g., a placebo layer is further added. If necessary, an additional coating (for example, film coating) may be performed on the resulting multi-layer tablet (e.g., bi-layer or triple-layer tablet).
The present invention also provides a process for preparing a capsule formulation, the process of which comprises: (i) coating aspirin or its salt with a coating solution to obtain aspirin-containing particles, wherein the coating solution comprises a copolymer of methacrylic acid and ethyl acrylate in a weight ratio of 1:1 or hydroxypropyl cellulose phthalate; (ii') coating clopidogrel or its salt with a coating solution to obtain clopidogrel-containing particles, wherein the coating solution comprises hydroxypropyl cellulose or hydroxypropyl methylcellulose, and then compressing the clopidogrel-containing particles and a pharmaceutically acceptable excipient to obtain clopidogrel-containing tablets; and (iii') filling a capsule with the aspirin-containing particles obtained in the step (i) and the clopidogrel-containing tablets obtained in the step (ii').
The step (i) and (ii') may be carried out changing the order or simultaneously. That is, the step (i) and (ii') may be carried out independently. The coatings of step (i) and (ii') may be performed according to conventional coating methods in the field of pharmaceutics, for example according to a fluid bed coating process. If necessary, an additional coating (for example, film coating) may be performed on the clopidogrel-containing tablets obtained in the step (ii'). The filling of step (iii') may be also performed according to conventional filling methods in the field of pharmaceutics.
The present invention will be described in further detail with reference to the following examples. These examples are for illustrative purposes only and are not intended to limit the scope of the present invention.
Example 1: Preparation of aspirin-containing particles
Aspirin-containing particles were prepared according to the components and amounts shown in Table 1. The aspirin granules used in Table 1 were Rhodine 2316TM (Rhodia). The used aspirin granules (1,111.1 g) correspond to 1,000.0 g of aspirin. Eudragit L30D55TM (Evonic), triethyl citrate, and talc were dissolved and dispersed in water to obtain a coating solution. The aspirin granules were coated with the coating solution, using a fluid bed granulator [GPCG-1 (GLATT, Germany)], under the following conditions: 40∼60 ℃ of inlet temperature, 25∼35℃ of outlet temperature, 25∼35℃ of product temperature, 2∼5 mL/min of spray rate.
Table 1
Example (g)
1-1 1-2 1-3 1-4 1-5 1-6 1-7
Aspirin granules 1,111.1 1,111.1 1,111.1 1,111.1 1,111.1 1,111.1 1,111.1
Eudragit L30D55TM(as dry powder) 185.3(55.6) 370.3(111.11) 555.6(166.7) 740.7(222.2) 925.9(277.8) 1,481.2(444.4) 1,851.8(555.6)
Triethyl citrate 5.6 11.1 16.7 22.2 27.8 44.4 55.6
Talc 27.8 55.6 83.3 111.1 138.9 222.2 277.8
Water 226 452 678 904 1,131 1,808 2,261
Example 2: Preparation of aspirin-containing particles
Aspirin-containing particles were prepared according to the components and amounts shown in Table 2. The aspirin granules used in Table 2 were Rhodine 2316TM (Rhodia). The used aspirin granules (1,111.1 g) correspond to 1,000.0 g of aspirin. Hydroxypropyl cellulose phthalate, triethyl citrate, and talc were dissolved and dispersed in a mixed solvent of ethanol and acetone (1:1) to obtain a coating solution. The aspirin granules were coated with the coating solution, using a fluid bed granulator [GPCG-1 (GLATT, Germany)], under the same conditions as in Example 1.
Table 2
Example (g)
2-1 2-2 2-3 2-4 2-5 2-6 2-7
Aspirin granules 1,111.1 1,111.1 1,111.1 1,111.1 1,111.1 1,111.1 1,111.1
Hydroxypropyl cellulose phthalate 55.6 111.1 166.7 222.2 277.8 333.3 444.4
Triethyl citrate 8.3 16.7 25.0 33.3 41.7 50.0 66.7
Talc 27.8 55.6 83.3 111.1 138.9 166.7 222.2
Ethanol 740 1,480 2,220 2,960 3,700 4,440 5,920
Acetone 740 1,480 2,220 2,960 3,700 4,440 5,920
Example 3: Preparation of aspirin-containing particles
(1) Preparation of aspirin pellets
Aspirin pellets were prepared according to the components and amounts shown in Table 3. Hydroxypropyl cellulose and aspirin were dissolved and dispersed in ethanol to obtain a coating solution. An inert core (Sugar spheres) was coated with the coating solution, using a fluid bed granulator [GPCG-1 (GLATT, Germany)] to obtain aspirin pellets. The coating conditions were as followings: 45∼60℃ of inlet temperature, 25∼35℃ of outlet temperature, 25∼35℃ of product temperature, 8 mL/min of spray rate.
Table 3
Example (g)
3-1 3-2
Sugar spheres 600 300
Aspirin 600 600
Hydroxypropyl cellulose 30 30
Ethanol 3000 3000
(2) Preparation of aspirin-containing particles
Aspirin-containing particles were prepared according to the components and amounts shown in Table 4. Hydroxypropyl cellulose phthalate, triethyl citrate, and talc were dissolved and dispersed in a mixed solvent of ethanol and acetone (1:1) to obtain a coating solution. The aspirin pellets were coated with the coating solution, using a fluid bed granulator [GPCG-1 (GLATT, Germany)], under the same conditions as in Example 1.
Table 4
Example (g)
3-3 3-4 3-5 3-6
Pellets of Example 3-1(aspirin) 1230(600)
Pellets of Example 3-1(aspirin) 930(600) 930(600) 930(600)
Hydroxypropyl cellulose phthalate 123.0 93.0 139.5 186
Triethyl citrate 12.3 9.3 14.0 18.6
talc 24.6 18.6 27.9 36.2
Ethanol 1285 970 1460 1945
Acetone 1285 970 1460 1945
Examples 4 and 5: Preparation of clopidogrel-containing particles
Clopidogrel-containing particles in a granule form were prepared according to the components and amounts shown in Table 5 and Table 6. The used clopidogrel hydrogen sulfate (978.75 g) corresponds to 750 g of clopidogrel. Hydroxypropyl methylcellulose (Pharmacoat 603TM, Shinetsu) was dispersed in a mixed solvent of ethanol and methylene chloride (1:1) to obtain a coating solution. The clopidogrel hydrogen sulfate was coated with the coating solution, using a fluid bed granulator [GPCG-1 (GLATT, Germany)], under the following conditions: 60∼70℃ of inlet temperature, 35∼45℃ of outlet temperature, 35∼45℃ of product temperature, 5 mL/min of spray rate.
Table 5
Example (g)
4-1 4-2 4-3 4-4 4-5 4-6 4-7 4-8
Clopidogrel hydrogen sulfate 978.75 978.75 978.75 978.75 978.75 978.75 978.75 978.75
Hydroxypropyl methylcellulose 3cps 21.25 51.25 117.25 181.25 241.25 301.25 391.50 489.50
Ethanol 121 293 670 1,036 1,379 1,721 2,237 2,796
Methylene chloride 121 293 670 1,036 1,379 1,721 2,237 2,796
Table 6
Example (g)
5-1 5-2 5-3 5-4 5-5 5-6 5-7 5-8
Clopidogrel hydrogen sulfate 978.75 978.75 978.75 978.75 978.75 978.75 978.75 978.75
Hydroxypropyl methylcellulose 6cps 21.25 51.25 117.25 181.25 241.25 301.25 391.50 489.50
Ethanol 121 293 670 1,036 1,379 1,721 2,237 2,796
Methylene chloride 121 293 670 1,036 1,379 1,721 2,237 2,796
Example 6: Preparation of clopidogrel-containing mini tablets
Clopidogrel-containing mini tablets were prepared according to the components and amounts shown in Table 7. The amounts of the table 7 refer to the amounts (in mg) per 1 mini tablet. A mixture of clopidogrel-containing particles (the particles obtained in Example 4-3), microcrystalline cellulose, and L-hydroxypropyl cellulose (L-HPC) was mixed with a mixture of Aerosil 200 and sodium stearyl fumarate. The resulting mixture was compressed to obtain mini tablets (diameter: 6 mm). The tablets of Example 6-2 and 6-3 were further film-coated. That is, hydroxypropyl methylcellulose, polyethylene glycol 6000, titanium dioxide, and iron oxide were dispersed in water to obtain a coating solution, with which the mini tablets were coated.
Table 7
Example (mg)
6-1 6-2 6-3
clopidogrel-containing particles Example 4-3 109.6 109.6 109.6
Excipient Microcrystalline cellulose 52.4 52.4 52.4
L-Hydroxypropyl cellulose 12.0 12.0 12.0
Aerosil 200 3.0 3.0 3.0
Sodium stearyl fumarate 3.0 3.0 3.0
Coating material Hydroxypropyl methylcellulose 8.0 16.0
Polyethylene glycol 6000 1.0 2.0
Titanium dioxide 0.9 1.8
Iron oxide 0.1 0.2
Total 180 190 200
Examples 7 and 8: Preparation of capsules
Capsules were prepared according to the components and amounts shown in Table 8 and Table 9. The amounts of the tables 8 and 9 refer to the amounts (in mg) per 1 capsule. Clopidogrel-containing particles were mixed with talc (and microcrystalline cellulose in case of Example 7-7) to obtain a mixture (mixture A). Aspirin-containing particles were mixed with talc to obtain a mixture (mixture B). The mixture A was filled in a # 1 capsule and then the mixture B was filled therein to prepare capsules.
Table 8
Example (mg)
7-1 7-2 7-3 7-4 7-5 7-6 7-7
Clopidogrel-containing particles Example 4-2 102.0
Example 4-3 109.6 109.6
Example 4-4 116.0
Example 4-5 122.0
Example 4-6 128.0
Example 4-7 137.0
Microcrystalline cellulose 37.0
Talc 4.0 4.4 5.0 5.0 5.0 5.0 4.4
Aspirin- containing particles Example 1-4 146.67 146.67 146.67 146.67 146.67 146.67 146.67
Talc 4.33 4.33 4.33 4.33 4.33 4.33 4.33
Total 257 265 272 278 284 293 302
Table 9
Example (mg)
8-1 8-2 8-3 8-4 8-5 8-6 8-7 8-8
Clopidogrel-containing particles Example 4-3 109.6 109.6 109.6 109.6 109.6 109.6 109.6 109.6
Talc 4.4 4.4 4.4 4.4 4.4 4.4 4.4 4.4
Aspirin- containing particles Example 1-2 128.89
Example 1-3 137.78
Example 1-4 146.67
Example 1-5 155.56
Example 1-6 182.21
Example 2-3 138.61
Example 2-4 147.77
Example 2-5 156.95
Talc 4.11 4.22 4.33 4.44 5.79 4.39 4.23 5.05
Total 247 256 265 274 302 257 266 276
Example 9: Preparation of capsules
Capsules were prepared according to the components and amounts shown in Table 10. The amounts of the table 10 refer to the amounts (in mg) per 1 capsule. The clopidogrel-containing tablets were manually filled in a # 1 capsule and then the aspirin-containing particles were filled therein to prepare capsules.
Table 10
Example (mg)
9-1 9-2 9-3 9-4
Clopidogrel-containing tablets Example 6-1 180.0 180.0
Example 6-3 200.0 200.0
Aspirin-containing particles Example 3-3 231.65 231.65
Example 3-4 175.15 175.15
Total 411.65 431.65 355.15 375.15
Example 10: Preparation of tablets
Tablets were prepared according to the components and amounts shown in Table 11. The amounts of the table 11 refer to the amounts (in mg) per 1 mini tablet. A mixture of clopidogrel-containing particles, aspirin-containing particles, microcrystalline cellulose, starch 1500, and L-hydroxypropyl cellulose (L-HPC) was mixed with a mixture of Aerosil 200 and stearic acid. The resulting mixture was compressed to obtain tablets.
Table 11
Example (mg)
10-1 10-2 10-3 10-4
Clopidogrel-containing particles Example 4-3 109.6 109.6
Example 5-3 109.6 109.6
Aspirin-containing particles Example 1-4 146.67 146.67
Example 2-4 147.77 147.77
Excipient Microcrystalline cellulose 114.73 114.73 113.63 113.63
Starch 1500 77 77 77 77
L-HPC 20 20 20 20
Aerosil 200 6 6 6 6
Stearic acid 6 6 6 6
Total 480 480 480 480
Comparative Examples 1 to 6: Preparation of capsules
Capsules were prepared in the same procedures as in Examples 7 and 8, according to the components and amounts shown in Table 12. In Comparative Example 1, the aspirin granules (111.11 mg) correspond to 100 mg of aspirin; and the clopidogrel hydrogen sulfate (97.875 mg) corresponds to 75 mg of clopidogrel.
Table 12
Comparative Example (mg)
1 2 3 4 5 6
Clopidogrel-containing particles Clopidogrel hydrogen sulfate 97.875
Example 4-1 100.0 101.0
Example 4-3 109.6 109.6
Example 4-8 146.8
Microcrystalline cellulose 20.125
Talc 5.0 4.0 6.2 4.4 4.4 4.0
Aspirin-containing particles Aspirin granule 111.11
Example 1-1 120.01 120.01
Example 1-4 146.67 146.67
Example 1-7 200.01
Talc 3.89 4.33 4.33 3.99 5.99 3.99
Total 238 255 304 238 320 229
Experimental Example 1: Evaluation of in vitro dissolution rate (clopidogrel)
The dissolution tests of the capsules prepared in Examples 7-1 to 7-7, 9-1, 9-2, 10-1, 10-2, and Comparative Example 3 were performed in a pH 2.0 buffer for 30 minutes. The dissolution rates (%) at 30 minutes are presented in the following tables 13 and 14.
Table 13
Example (%) Comparative Example
7-1 7-2 7-3 7-4 7-5 7-6 7-7 3
pH2.0 100.2 100.6 95.7 88.3 85.3 81.7 100.1 61.3
Table 14
Example (%)
9-1 9-2 10-1 10-2
pH2.0 97.6 92.1 99.9 98.4
As shown in Table 13, the capsules prepared from the clopidogrel-containing particles, in which hydroxypropyl methylcellulose was coated in amount of less than 40 parts by weight, based on 100 parts by weight of clopidogrel hydrogen sulfate, showed good dissolution rate, i.e., more than 80% of dissolution rate, which is a US Pharmacopeia (USP) standard. However, the capsule (i.e., the capsule of Comparative Example 3) prepared from the clopidogrel-containing particles, in which hydroxypropyl methylcellulose was coated in amount of more than 40 parts by weight, based on 100 parts by weight of clopidogrel hydrogen sulfate, showed remarkably reduced dissolution rate. And, as shown in Table 14, the capsules filled with the mini tablet obtained from the clopidogrel-containing particles; and the tablets prepared by compressing the clopidogrel-containing particles also showed good dissolution rate, i.e., more than 80% of dissolution rate, which is a US Pharmacopeia (USP) standard.
Experimental Example 2: Evaluation of in vitro dissolution rate (aspirin)
The dissolution tests of the capsules prepared in Examples 8-1 to 8-8, 9-1, 9-3, 10-1, 10-3, and Comparative Examples 1, 4, 5 were performed. Specifically, initial dissolution tests of the respective capsules were performed in a pH 1.0 buffer for 2 hours; and then the consecutive dissolution tests of the respective remaining formulations were performed in a pH 6.8 buffer (obtained by adding a 0.2M sodium phosphate tribasic solution to each dissolution medium) for 90 minutes. The dissolution rates (%) are presented in the following tables 15 and 16.
Table 15
Example Comparative Example
8-1 8-2 8-3 8-4 8-5 8-6 8-7 8-8 1 4 5
pH1.0 9.4 5.9 4.0 3.2 2.5 5.4 4.6 3.9 96.5 18.9 1.2
pH6.8 92.7 102.2 100.3 89.7 82.8 101.2 99.7 93.8 98.0 102.3 74.5
Table 16
Example
9-1 9-3 10-1 10-3
pH1.0 2.0 1.8 7.8 8.5
pH6.8 95.8 98.0 95.2 96.5
As shown in Table 15, the capsules prepared according to the present invention showed low dissolution rate, i.e., less than 10% of dissolution rate in a pH 1.0 buffer and high dissolution rate in a pH 6.8 buffer. In contrast, in case of the capsule prepared from non-coated aspirin (i.e., the capsule of Comparative Example 1), most of aspirin was dissolved in a pH 1.0 buffer. And also, in case of the capsule prepared from the aspirin-containing particles having the coating agent in an amount of less than 10 parts by weights based on 100 parts by weight of aspirin granule (i.e., the capsule of Comparative Example 4), more than 10% of aspirin was dissolved in a gastric acid condition. And also, the capsule prepared from the aspirin-containing particles having the coating agent in an amount of more than 40 parts by weights based on 100 parts by weight of aspirin granule (i.e., the capsule of Comparative Example 5) showed poor dissolution rate in a pH 6.8 buffer, i.e., less than 80% of dissolution rate, although aspirin was not dissolved in a gastric acid condition significantly. And, as shown in Table 16, the capsules containing the aspirin-containing particles obtained from the aspirin pellets; and the tablets prepared by compressing the aspirin-containing particles showed low dissolution rate, i.e., less than 10% of dissolution rate in a pH 1.0 buffer; and good dissolution rate, i.e., more than 80% of dissolution rate in a pH 6.8 buffer, which is a US Pharmacopeia (USP) standard.
Experimental Example 3: Stability test
Stabilities of the capsules prepared in Examples 7-2, 7-6, 8-3, 8-7 and Comparative Examples 1, 2, 4, 6 were evaluated under accelerated conditions (40 ℃, a relative humidity of 75 %) for 1 month. The stability test results are shown in Table 17 (contents, %) and Table 18 (impurities, %). In Table 18, the impurities A and C represent the degradation products originated from clopidogrel; and salicylic acid represents the degradation product of aspirin.
Table 17 Contents of active ingredients (under accelerated conditions for 1 month)
Storage condition Ingredient Example Comparative Example
7-2 7-6 8-3 8-7 1 2 4 6
0 month Clopidogrel 100.7 100.9 101.0 100.3 99.8 100.1 100.2 101.2
Aspirin 100.1 100.4 99.9 99.5 100.2 100.7 100.8 100.8
Accelerated conditions for 1 month Clopidogrel 99.9 99.4 100.2 100.7 92.7 96.5 99.1 94.2
Aaspirin 101.4 102.0 100.6 99.9 83.2 99.6 94.2 89.3
Table 18 Contents of impurities (under accelerated conditions for 1 month)
Storage condition Impurity Example Comparative Example
7-2 7-6 8-3 8-7 1 2 4 6
0 month Impurity A 0.12 0.13 0.13 0.12 0.13 0.13 0.12 0.12
Impurity C 0.09 0.08 0.09 0.10 0.10 0.10 0.09 0.09
Salicylic acid 0.10 0.11 0.10 0.10 0.11 0.11 0.12 0.10
Total impurities 0.31 0.32 0.32 0.31 0.33 0.34 0.33 0.34
Accelerated conditions for 1 month Impurity A 0.15 0.14 0.14 0.14 1.14 0.33 0.26 0.56
Impurity C 0.10 0.09 0.09 0.09 0.38 0.21 0.19 0.23
Salicylic acid 0.39 0.38 0.40 0.39 7.53 1.88 2.99 5.10
Total impurities 0.61 0.64 0.62 0.63 9.14 2.33 3.54 5.87
As shown in Table 17 and Table 18, in case of the capsule prepared with no pharmaceutical treatment (i.e., the capsule of Comparative Example 1), the stabilities of both drugs were remarkably reduced due to the drug interaction thereof. And also, in case of the capsule in which both drugs were coated with relatively low amounts of the coating agents (i.e., the capsule of Comparative Example 6), the stabilities of both drugs were still poor. In case of the capsule prepared from the clopidogrel-containing particles having less than 5 parts by weigh of the coating agent based on 100 parts by weight of clopidogrel hydrogen sulfate (i.e., the capsule of Comparative Example 2), the amounts of clopidogrel-originated degradation products were remarkably increased; and the amount of salicylic acid was also slightly increased. In case of the capsule prepared from the aspirin-containing particles having less than 5 parts by weight of the coating agent based on 100 parts by weight of aspirin granules (i.e., the capsule of Comparative Example 4), the amount of salicylic acid was remarkably increased. In contrast, the capsules prepared according to the present invention (i.e., the capsules of Example 7-2, 7-6, 8-3, and 8-7) exhibited excellent stability profiles, showing little change in contents of the active ingredients and very low formation of degradation products.

Claims (12)

  1. A pharmaceutical composition comprising (a) aspirin-containing particles having a coating layer formed on aspirin or its salt, wherein the coating layer comprises a copolymer of methacrylic acid and ethyl acrylate in a weight ratio of 1:1 or hydroxypropyl cellulose phthalate; and (b) clopidogrel-containing particles having a coating layer formed on clopidogrel or its salt, wherein the coating layer comprises hydroxypropyl cellulose or hydroxypropyl methylcellulose.
  2. The pharmaceutical composition according to claim 1, wherein the aspirin or its salt is in a granule form or in a pellet form.
  3. The pharmaceutical composition according to claim 1, wherein the copolymer of methacrylic acid and ethyl acrylate in a weight ratio of 1:1 or hydroxypropyl cellulose phthalate is present in an amount ranging from 10 to 40 parts by weight, based on 100 parts by weight of aspirin or its salt.
  4. The pharmaceutical composition according to claim 1, wherein the hydroxypropyl cellulose or hydroxypropyl methylcellulose is present in an amount ranging from 5 to 40 parts by weight, based on 100 parts by weight of clopidogrel or its salt.
  5. The pharmaceutical composition according to claim 1, wherein the aspirin-containing particles and/or the clopidogrel-containing particles are in a powder form, in a granule form, in a pellet form, or in a mini tablet form.
  6. The pharmaceutical composition according to claim 1, wherein the clopidogrel-containing particles are in a mini tablet form.
  7. The pharmaceutical composition according to any one of claims 1 to 6, having a dosage form of capsule, tablet, or granule.
  8. A process for preparing a pharmaceutical composition, the process of which comprises:
    (i) coating aspirin or its salt with a coating solution to obtain aspirin-containing particles, wherein the coating solution comprises a copolymer of methacrylic acid and ethyl acrylate in a weight ratio of 1:1 or hydroxypropyl cellulose phthalate;
    (ii) coating clopidogrel or its salt with a coating solution to obtain clopidogrel-containing particles, wherein the coating solution comprises hydroxypropyl cellulose or hydroxypropyl methylcellulose; and
    (iii) forming capsules, tablets, or granules using the aspirin-containing particles obtained in the step (i), the clopidogrel-containing particles obtained in the step (ii), and optionally a pharmaceutically acceptable excipient.
  9. A process for preparing a capsule formulation, the process of which comprises:
    (i) coating aspirin or its salt with a coating solution to obtain aspirin-containing particles, wherein the coating solution comprises a copolymer of methacrylic acid and ethyl acrylate in a weight ratio of 1:1 or hydroxypropyl cellulose phthalate;
    (ii') coating clopidogrel or its salt with a coating solution to obtain clopidogrel-containing particles, wherein the coating solution comprises hydroxypropyl cellulose or hydroxypropyl methylcellulose, and then compressing a mixture of the clopidogrel-containing particles and a pharmaceutically acceptable excipient to obtain clopidogrel-containing tablets; and
    (iii') filling a capsule with the aspirin-containing particles obtained in the step (i) and the clopidogrel-containing tablets obtained in the step (ii').
  10. The process according to claim 8 or 9, wherein the aspirin or its salt is in a granule form or in a pellet form.
  11. The process according to claim 8 or 9, wherein the coating solution of step (i) comprises a copolymer of methacrylic acid and ethyl acrylate in a weight ratio of 1:1 or hydroxypropyl cellulose phthalate in an amount ranging from 10 to 40 parts by weight, based on 100 parts by weight of aspirin or its salt.
  12. The process according to claim 8 or 9, wherein the coating solution of step (ii') comprises hydroxypropyl cellulose or hydroxypropyl methylcellulose in an amount ranging from 5 to 40 parts by weight, based on 100 parts by weight of clopidogrel or its salt.
PCT/KR2013/001792 2012-03-09 2013-03-06 Pharmaceutical composition comprising clopidogrel and aspirin and process for preparing the same WO2013133620A1 (en)

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CN105311038A (en) * 2014-07-14 2016-02-10 天津药物研究院 Pharmaceutical composition containing clopidogrel hydrogen sulfate and aspirin, and preparation method thereof
CN106324114A (en) * 2015-06-30 2017-01-11 天津药物研究院有限公司 Detection method for clopidogrel hydrogen sulfate specific impurities in compound preparation
CN109069436A (en) * 2016-03-16 2018-12-21 韩国联合制药株式会社 Compound formulation containing clopidogrel and aspirin
CN115737578A (en) * 2022-11-23 2023-03-07 石家庄四药有限公司 Clopidogrel hydrogen sulfate and aspirin compound tablet and preparation method thereof
CN115770229A (en) * 2022-12-13 2023-03-10 山东诺明康药物研究院有限公司 Clopidogrel sulfate aspirin tablet and preparation method and application thereof

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WO2015015062A1 (en) * 2013-08-02 2015-02-05 Sanofi Pharmaceutical tablet comprising acetylsalicylic acid and clopidogrel
KR101764785B1 (en) * 2015-05-29 2017-08-07 한국유나이티드제약 주식회사 Pharmaceutical combination preparation

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US20070003615A1 (en) * 2005-06-13 2007-01-04 Elan Pharma International Limited Nanoparticulate clopidogrel and aspirin combination formulations
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CN105311038A (en) * 2014-07-14 2016-02-10 天津药物研究院 Pharmaceutical composition containing clopidogrel hydrogen sulfate and aspirin, and preparation method thereof
CN106324114A (en) * 2015-06-30 2017-01-11 天津药物研究院有限公司 Detection method for clopidogrel hydrogen sulfate specific impurities in compound preparation
CN109069436A (en) * 2016-03-16 2018-12-21 韩国联合制药株式会社 Compound formulation containing clopidogrel and aspirin
CN115737578A (en) * 2022-11-23 2023-03-07 石家庄四药有限公司 Clopidogrel hydrogen sulfate and aspirin compound tablet and preparation method thereof
CN115770229A (en) * 2022-12-13 2023-03-10 山东诺明康药物研究院有限公司 Clopidogrel sulfate aspirin tablet and preparation method and application thereof

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