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WO2013065936A1 - Agent complexe contenant du clopidogrel et de l'aspirine - Google Patents

Agent complexe contenant du clopidogrel et de l'aspirine Download PDF

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Publication number
WO2013065936A1
WO2013065936A1 PCT/KR2012/006316 KR2012006316W WO2013065936A1 WO 2013065936 A1 WO2013065936 A1 WO 2013065936A1 KR 2012006316 W KR2012006316 W KR 2012006316W WO 2013065936 A1 WO2013065936 A1 WO 2013065936A1
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WIPO (PCT)
Prior art keywords
aspirin
clopidogrel
acid
mixtures
group
Prior art date
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Ceased
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PCT/KR2012/006316
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English (en)
Korean (ko)
Inventor
정원태
최연웅
남규열
박상만
하대철
도남혁
이성능
신경도
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Korea United Pharm Inc
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Korea United Pharm Inc
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Priority to CN201280053817.4A priority Critical patent/CN103957895A/zh
Publication of WO2013065936A1 publication Critical patent/WO2013065936A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • 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
    • A61K31/33—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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4743—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having sulfur as a ring hetero atom
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/167—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface
    • 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 combination formulation comprising clopidogrel and aspirin. Specifically, the present invention relates to a stable and bioavailable composite formulation containing a granule coated with a clopidogrel layer as an immediate protective layer and an aspirin granule coated with an aspirin layer as an enteric layer.
  • Clopidogrel ie, methyl (+)-(S) - ⁇ - (2-chlorophenyl) -6,7-dihydrothieno [3,2-c] pyridine-5 (4H) -acetate, is known to cause stroke, thrombosis and embolism
  • platelet aggregation inhibitors are effective in the treatment of coronary artery diseases such as stroke, thrombosis, embolism and myocardial infarction.
  • Clopidogrel inhibits ADP-induced platelet aggregation by direct inhibition of ADP binding to adenosine diphosphate (ADP) receptors and subsequent direct inhibition of ADP-mediated activation of the glycoprotein GPIIb / IIa complex.
  • ADP adenosine diphosphate
  • Clopidogrel also inhibits platelet aggregation caused by agonists other than ADP by blocking amplification of platelet activation by released ADP.
  • clopidogrel The pharmacological action of clopidogrel is caused by an active metabolite formed by metabolism in the liver after oral administration of clopidogrel.
  • This active metabolite selectively and irreversibly modifies the ADP receptor on platelets, thereby preventing ADP from binding to the ADP receptor. Therefore, the effect of clopidogrel is highly dependent on the enzyme that metabolizes clopidogrel in the liver.
  • clopidogrel bisulfate a representative pharmaceutical ingredient of clopidogrel, is methyl (+)-(S) - ⁇ - (2-chlorophenyl) -6,7-dihydrothieno [3,2-c] pyridine-5 ( 4H) -acetate sulfate (1: 1).
  • the empirical formula of clopidogrel bisulfate is C 16 H 16 ClNO 2 S.H 2 SO 4 , and its molecular weight is 419.9.
  • Clopidogrel bisulfate is a white to gray powder. It is substantially insoluble in water at neutral pH, but very soluble at pH 1.0. It is also well soluble in methanol, slightly soluble in methylene chloride and substantially insoluble in ethyl ether.
  • Clopidogrel bisulfate is prescribed for the reduction of thrombotic events, such as acute myocardial infarction (MI), acute stroke, or established arterial disease, It has been found to reduce the rate of the combined end point of new ischemic stroke, new MI, and other vascular deaths.
  • MI myocardial infarction
  • clopidogrel bisulfate may cause cardiovascular death, MI, or the rate of complex endpoints of stroke, as well as cardiovascular death, MI, stroke, or refractory ischemia. It has been found to reduce the speed of the combined endpoints.
  • Aspirin also known as acetylsalicylic acid, is often used as an analgesic (for mild pain and pain), antipyretics (for fever), and anti-inflammatory agents. Aspirin also has an anticoagulant (blood thinning) effect and is used to prevent heart attacks at long, low doses.
  • Aspirin having CAS number 50-78-2 is chemically known as 2-acetoxybenzoic acid. Aspirin has a molecular formula of C 9 H 8 O 4 and has a molecular weight of 180.16.
  • Aspirin is colorless or white crystals or white crystalline powder or granules. Aspirin is odorless or slightly acidic. Aspirin has a melting point of 136 ° C and a boiling point of 140 ° C. Aspirin is free acid, acetanilide, aminopyrin, phenazone, hexamine, iron salt, phenobarbitone sodium, quinine salt, potassium and sodium iodine, and alkali hydroxides, carbonates, and stearates Incompatible with Acetylsalicylic acid is stable in dry air, but upon contact with moisture it is gradually hydrolyzed to acetic acid and salicylic acid.
  • Aspirin is prescribed as an analgesic for the treatment of mild to moderate pain, as an anti-inflammatory agent for the treatment of soft tissues and joint inflammation, and as a drug for antipyretics.
  • Aspirin is generally administered in doses of up to 4 g per day at 300-1000 mg every four hours in adults with pain and fever.
  • administration is generally given 1 g six times a day and up to 8 g per day.
  • administration is generally given from 0.5 g to 1 g six times a day and up to 8 g per day.
  • administration is generally administered from 300 mg to 1200 mg per day in two or three doses.
  • Aspirin can be used to reduce the likelihood of heart attacks, strokes, or other problems that can occur when blood vessels are blocked by blood clots. Aspirin prevents the formation of dangerous blood clots.
  • aspirin is known to activate enzymes that convert clopidogrel into an active metabolite in the liver. Therefore, many studies have been made on the formulation of clopidogrel and aspirin, but there is a problem that eutectic phenomenon occurs when the two drugs are in direct contact. First of all, aspirin is a substance that absorbs a small amount of gastrointestinal absorption, but aspirin itself has a property that hurts the stomach, so the amount of use is considerable. This problem is exacerbated in formulations in which aspirin is first eluted for metabolism of clopidogrel.
  • cytochrome P450 2C19 CYP450 2C19
  • hepatic metabolase activated by pre-release aspirin has individual differences in the degree of production of the active metabolites, and these individual differences inevitably affect the drug blood concentration of the active metabolites. Cause deviation. And, this deviation is undesirable because it is uncontrollable and may have an unpredictable effect on the patient.
  • Patent Document 1 KR 10-2009-0091076 A (Hanol Pharmaceutical Co., Ltd.) 2009.8.26.
  • Patent Document 2 WO 2006/138214 A (Elan Perm International Limited) 2006.12.28.
  • Patent Document 3 WO 2000/66130 A (Sanopy-Sindelabo) 2000.11.9.
  • Patent Document 4 WO 1997/29753 A (Sanopy D. Kosch) 1997.8.21.
  • the present invention has been made in order to solve the above problems, a stable and bioavailable composite formulation containing the granules coated with the clopidogrel layer as a rapid protective layer and the granules coated with the aspirin layer in the enteric layer together in a capsule Its purpose is to provide.
  • a clopidogrel outer core Adjacent to the outer core, a clopidogrel outer core comprising clopidogrel, an isomer thereof or a pharmaceutically acceptable salt thereof and a first binder as a pharmacologically active ingredient, and
  • Immediate protective layer adjacent to the outside of the outer core comprising a second binder and a first plasticizer
  • Clopidogrel granules including
  • the clopidogrel outer core may further comprise a third plasticizer.
  • the aspirin extranucleus may further comprise a fourth plasticizer.
  • the excipient may be selected from the group consisting of sugar, starch, microcrystalline cellulose, lactose, carnauba wax, mannitol, tartaric acid, xylitol, and mixtures thereof.
  • the pharmaceutically acceptable salt of clopidogrel may be selected from the group consisting of hydrogen sulfate, resinate, campylate, besylate, napadisylate monohydrate salt, hydrochloride and mixtures thereof.
  • first binder, the second binder and the third binder are each independently selected from the group consisting of substituted or unsubstituted alkyl cellulose or a salt thereof, polyvinyl derivative, polyalkylene glycol, polymethacrylic acid and mixtures thereof. Can be.
  • substituted or unsubstituted alkyl cellulose or salts thereof include methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, methyl hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose sodium and mixtures thereof. It may be selected from the group consisting of.
  • polyvinyl derivative may be selected from the group consisting of polyvinylpyrrolidone, polyvinyl alcohol and mixtures thereof.
  • polyalkylene glycol may be selected from the group consisting of polyethylene glycol, polypropylene glycol and mixtures thereof.
  • the polymethacrylic acid may be poly (butylmethacrylic acid-co- (2-dimethylaminoethyl) methacrylic acid-co-methylmethacrylic acid), poly (ethylacrylic acid-co-methylmethacrylic acid), poly ( Ethylacrylic acid-co-methylmethacrylic acid-co-trimethylaminoethylmethacrylic chloride) and mixtures thereof.
  • first plasticizer, the second plasticizer, the third plasticizer and the fourth plasticizer may be independently selected from the group consisting of glycol, ester, oil, glycerin, glycerin derivatives and mixtures thereof.
  • glycol may be selected from the group consisting of propylene glycol, polyethylene glycol and mixtures thereof.
  • ester may be selected from the group consisting of diethyl phthalate, dibutyl phthalate, dibutyl sebacate, triethyl citrate, acetyltriethyl citrate, acetyltributyl citrate, triacetin and mixtures thereof.
  • the oil may be selected from the group consisting of castor oil, coconut oil and mixtures thereof.
  • glycerin and glycerin derivative may be selected from the group consisting of glycerin, glycerin monostearate and mixtures thereof.
  • the enteric coating agent is shellac, hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, cellulose acetate phthalate, cellulose acetate, polyvinyl alcohol phthalate, poly (methacrylic acid-co-methyl methacrylate), Poly (methylacrylic acid-co-methylmethacrylic acid-co-methacrylic acid), poly (methacrylic acid-co-ethylacrylic acid), and mixtures thereof.
  • clopidogrel outer core, aspirin outer core, immediate protective layer or enteric layer may further include an additive selected from the group consisting of diluents, lubricants, stabilizers, film coating agents and mixtures thereof.
  • aspirin may be 10 to 1000 parts by weight based on 100 parts by weight of the clopidogrel.
  • the capsule may be a hard capsule.
  • immediately protective layer is applied to the outer surface of the clopidogrel outer core to prevent clopidogrel from directly contacting aspirin (protective layer) while simultaneously releasing the cropidogrel from the top (rapid release). Means a layer that plays a role in helping to become a member.
  • the combination formulation of the present invention is filled with clopidogrel and aspirin in one capsule, but clopidogrel is filled with immediate release granules and enteric granules with aspirin to prevent direct physical contact between the main components, clopidogrel and aspirin.
  • the biggest feature is that it blocks the eutectic at the source. By eliminating eutectic like this, it is possible to prevent the change of the physicochemical properties of each component, thereby preventing the change of the content, dissolution characteristics and bioequivalence of the formulation in the short term, and improve the stability of the formulation in the long term.
  • the combination preparation of the present invention coated aspirin with an enteric layer so that aspirin elutes only in the intestine and does not elute in the stomach, in order to prevent the problem of aspirin irritating the stomach wall and causing damage. Therefore, oral administration of the combination preparation of the present invention, clopidogrel is eluted from the stomach first, aspirin is eluted later in the intestine has the effect of preventing gastric wall damage.
  • the combination preparation of the present invention can increase the ease and compliance of taking the drug compared to the case of taking clopidogrel and aspirin at the same time or at the same time, respectively, and due to the pharmacological action of two complementary drugs, The same result can be obtained with a smaller dose, and there are advantages of reducing side effects and manufacturing cost due to pharmacological components.
  • 1 is a schematic diagram of the structure of the co-formulation of the present invention.
  • Figure 5 is a graph of the change in the content of clopidogrel in 6 months accelerated test.
  • Figure 6 is a graph of the change in the content of aspirin in the 6 month accelerated test.
  • 9 is a graph showing the change in dissolution rate of aspirin in pH 6.8 in the 6 month accelerated test.
  • FIG. 10 is a graph showing the change in total lead content of clopidogrel in the 6 month accelerated test.
  • Figure 11 is a graph of the total amount of analogues of aspirin in 6 months accelerated test.
  • Figure 12 Clopidogrel granules and flavix Comparative elution graph at pH 1.2 against tablets.
  • FIG. 13 shows clopidogrel granules and flavix Comparative elution graph at pH 4.0 for tablets.
  • Figure 15 Clopidogrel granules and flavix A graph of comparative elution in water against tablets.
  • 16 is aspirin granules and astrix Comparative elution graph at pH 1.2 for capsules.
  • 17 is aspirin granules and astrix Comparative elution graph at pH 6.0 for capsules.
  • 19 is a graph of blood concentration of clopidogrel.
  • 20 is a graph of blood concentration of aspirin.
  • 21 is a graph of blood concentration of salicylic acid.
  • the co-formulation of the present invention includes clopidogrel granules and aspirin granules in capsules, as shown in FIG.
  • a clopidogrel outer core comprising an isomer thereof or a pharmaceutically acceptable salt thereof and a first binder, and an immediate protective layer adjacent to the outside of the outer core and including a second binder and a first plasticizer.
  • the aspirin granules are adjacent to the inner core, including an excipient, adjacent to the outer core, and adjacent to the outer core, including an aspirin or a pharmaceutically acceptable salt thereof and a third binder as a pharmacologically active ingredient.
  • an enteric layer comprising an enteric coating and a second plasticizer.
  • Such a co-formulation of the present invention is first eluted clopidogrel granules in the stomach, aspirin granules are later eluted in the intestine.
  • aspirin granules are later eluted in the intestine.
  • gastric wall damage caused by aspirin can be prevented.
  • the eutectic can be prevented, thereby preventing changes in content or dissolution characteristics and improving the stability of the drug.
  • the clopidogrel outer core may further include a third plasticizer
  • the aspirin outer core may further include a fourth plasticizer.
  • the excipient may be selected from the group consisting of sugar, starch, microcrystalline cellulose, lactose, carnauba wax, mannitol, tartaric acid, xylitol and mixtures thereof, with sugar being particularly preferred.
  • the pharmaceutically acceptable salt of clopidogrel may be selected from the group consisting of hydrogen sulfate, resinate, campylate, besylate, napadisylate monohydrate salt, hydrochloride, and mixtures thereof, in particular hydrogen sulfate. And besylates are preferred.
  • first binder, the second binder and the third binder are each independently selected from the group consisting of substituted or unsubstituted alkyl cellulose or a salt thereof, polyvinyl derivative, polyalkylene glycol, polymethacrylic acid and mixtures thereof.
  • the substituted or unsubstituted alkyl cellulose or a salt thereof may be methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, methyl hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, or carboxymethyl cellulose sodium. , Salts thereof and mixtures thereof, with hydroxypropylmethylcellulose being particularly preferred.
  • the polyvinyl derivative may be selected from the group consisting of polyvinylpyrrolidone, polyvinyl alcohol and mixtures thereof, and the polyalkylene glycol may be selected from the group consisting of polyethylene glycol, polypropylene glycol and mixtures thereof. have.
  • the polymethacrylic acid may be poly (butylmethacrylic acid-co- (2-dimethylaminoethyl) methacrylic acid-co-methylmethacrylic acid), poly (ethylacrylic acid-co-methylmethacrylic acid), poly ( Ethylacrylic acid-co-methylmethacrylic acid-co-trimethylaminoethylmethacrylic chloride) and mixtures thereof.
  • Poly (butylmethacrylic acid-co- (2-dimethylaminoethyl) methacrylic acid-co-methylmethacrylic acid) of the polymethacrylic acid is Eudragit E 100, Eudragit E 12.5, or Eudragit of Evonik Degussa (Germany). More preferred is poly (butylmethacrylic acid-co- (2-dimethylaminoethyl) methacrylic acid-co-methylmethacrylic acid) 1: 2: 1 such as E PO.
  • the poly (ethylacrylic acid-co-methylmethacrylic acid) is poly (ethylacrylic acid-co-methylmethacrylic acid) 2: 1 such as Eudragit NE 30D, Eudragit NE 40D, Eudragit NM 30D from Evonik Degussa (Germany). This is more preferable.
  • the poly ethylacrylic acid-co-methylmethacrylic acid-co-trimethylaminoethylmethacrylic chloride
  • Edranik RL 100 Eudragit RL PO
  • Eudragit RL 30D Eudragit RL 12.5 of Evonik Degussa (Germany).
  • first plasticizer, the second plasticizer, the third plasticizer and the fourth plasticizer may be independently selected from the group consisting of glycols, esters, oils, glycerin, glycerin derivatives and mixtures thereof, wherein glycol is propylene glycol , Polyethylene glycol and mixtures thereof, and esters are diethyl phthalate, dibutyl phthalate, dibutyl sebacate, triethyl citrate, acetyltriethyl citrate, acetyltributyl citrate, triacetin and The mixture may be selected from the group consisting of.
  • the oil may be selected from the group consisting of castor oil, coconut oil, and mixtures thereof, and glycerin and glycerin derivatives may be selected from the group consisting of glycerin, glycerin monostearate, and mixtures thereof.
  • the enteric coating agent is shellac, hydroxypropyl methyl cellulose acetate succinate, hydroxy propyl methyl cellulose phthalate, cellulose acetate phthalate, cellulose acetate, polyvinyl alcohol phthalate, poly (methacrylic acid-co-methyl methacrylate), Poly (methylacrylic acid-co-methylmethacrylic acid-co-methacrylic acid), poly (methacrylic acid-co-ethylacrylic acid), and mixtures thereof.
  • poly (methacrylic acid-co-methylmethacrylic acid) is poly (methacrylic acid-co-methylmethacrylic acid) such as Eudragit L 100, Eudragit L 12.5, Eudragit L 100 P of Evonik Degussa (Germany) 1 : 1, but poly (methacrylic acid-co-methylmethacrylic acid) 1: 2 such as Eudragit S 100, Eudragit S 12.5, and Eudragit S 100 P is more preferred.
  • poly (methylacrylic acid-co-methylmethacrylic acid-co-methacrylic acid) is poly (methylacrylic acid-co-methylmethacrylic acid-co-methacrylic acid) such as Eudragit FS 30D of Evonik Degussa (Germany). 7: 3: 1 is more desirable.
  • poly (methacrylic acid-co-ethylacrylic acid) is a poly (methacrylic acid-co-ethylacrylic acid) 1: 1 such as Eudragit L 30 D-55 and Eudragit L 100-55 of Evonik Degussa (Germany). More preferred.
  • clopidogrel outer core, aspirin outer core, immediate protective layer or enteric layer may further include an additive selected from the group consisting of diluents, lubricants, stabilizers, film coating agents and mixtures thereof.
  • the diluent is calcium carbonate, calcium phosphate, cellulose, dextrin, dextrose, ethyl cellulose, fructose, glyceryl palmitostearate, maltose, sucrose, starch, microcrystalline cellulose, lactose, glucose, mannitol, alginate, Alkaline earth metal salts, clay, polyethylene glycol, dicalcium phosphate and mixtures thereof.
  • the glidant may be selected from the group consisting of talc, stearic acid and its salts, sodium lauryl sulfate, hydrogenated vegetable oil, sodium benzoate, sodium stearyl fumarate, glyceryl monostearate, polyethylene glycol and mixtures thereof.
  • the stabilizer can be selected from the group consisting of butylated hydroxy toluene (BHT), butylated hydroxy anisole (BHA), ascorbic acid, tocopherol, edetic acid (EDTA) and mixtures thereof.
  • BHT butylated hydroxy toluene
  • BHA butylated hydroxy anisole
  • EDTA edetic acid
  • the film coating agent is gelatin, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyethylene glycol, shellac, ethyl cellulose, methyl hydroxyethyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose sodium, polyvinyl alcohol, polyvinyl Pyrrolidone, a polymer of vinylpyrrolidone and vinyl acetate, ethyl acrylate, methyl methacrylate, trimethylammonium chloride ethyl copolymer (for example, trade name Eudragit RS or RL, Evonik Degussa), methyl methacrylate and acrylic acid Ethyl copolymer (e.g., Eudragit NE30D, Evonik Degussa), polyvinylacetyldimethylaminoacetate, and mixtures thereof.
  • Eudragit RS or RL trade name Eudragit RS or RL, Evonik Deguss
  • the clopidogrel outer core, immediate release protective layer or clopidogrel outer core and immediate release protective layer may further include a rapid release material to increase the release rate, and the rapid release material may be a disintegrant, a foaming agent, a buffer, and the like. It can be chosen from mixtures.
  • the disintegrant may be a starch or modified starch such as sodium starch glycolate, corn starch, potato starch or starch gelatinized starch, clay such as bentonite, montmorillonite, veegum, microcrystalline cellulose, hydroxypropyl cellulose or Celluloses such as carboxymethyl cellulose, alginic acids such as sodium alginate or alginic acid, cross-linked celluloses such as croscarmellose sodium, gums such as guar gum and xanthan gum, and crosslinked polyvinylpyrrolidone ( crospovidone) and mixtures thereof.
  • starch or modified starch such as sodium starch glycolate, corn starch, potato starch or starch gelatinized starch, clay such as bentonite, montmorillonite, veegum, microcrystalline cellulose, hydroxypropyl cellulose or Celluloses such as carboxymethyl cellulose, alginic acids such as sodium alginate or alginic acid, cross-linked
  • the blowing agent may include a carbonic acid-containing inorganic material and an organic acid.
  • the inorganic carbonate-containing mineral may be selected from the group consisting of sodium hydrogen carbonate, sodium carbonate, calcium carbonate, potassium carbonate, magnesium carbonate, calcium hydrogen carbonate, potassium hydrogen carbonate and mixtures thereof.
  • 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 mixtures thereof.
  • the buffer is selected from the group consisting of calcium carbonate, sodium dihydrogen phosphate, sodium dihydrogen phosphate, sodium glutamate, potassium citrate, sodium bicarbonate, sodium citrate, sodium hydroxide, calcium phosphate, calcium hydrogen phosphate, or various salts and mixtures thereof. Can be.
  • aspirin may be 10 to 1000 parts by weight based on 100 parts by weight of the clopidogrel, and the capsule may be a hard capsule.
  • FIG. 2 is a differential scanning calorimetry graph for clopidogrel
  • FIG. 3 is a graph for aspirin
  • FIG. 4 is a graph for a mixture of two substances.
  • the melting point of clopidogrel hydrogen sulfate is 178.50 ° C.
  • the melting point of aspirin is 142.83 ° C., but the melting point decreases to 128.41 ° C. as the peaks merge. Therefore, the two pharmacologically active substances can be confirmed that the eutectic occurs, it can be seen that the formulation that can block the direct contact.
  • clopidogrel granules were prepared.
  • Stability was evaluated by performing an accelerated test (temperature 40 ⁇ 2 ° C., relative humidity 75 ⁇ 5%) for 6 months for the composite preparation of the present invention prepared by the above example, and the evaluation results are shown in FIGS. 5 to 11. Shown in 5 and 6 are the results of observing the changes in the content of clopidogrel and aspirin at intervals of 2 months, respectively, and after 6 months it can be seen that the content change is maintained at less than 1%.
  • FIG. 7 shows the change in dissolution rate of clopidogrel at two month intervals
  • FIG. 8 shows the change in dissolution rate of aspirin in 0.1N HCl solution
  • FIG. 9 at pH 6.8. No change was observed.
  • FIG. 10 shows the change in the amount of analogues of clopidogrel at two month intervals
  • FIG. 11 shows the change in the amount of analogues of aspirin. Similarly, no significant changes were observed after 6 months.
  • CPCS001, CPCS002, and CPCS003 described in the graphs of Figs. 5 to 11 are batch numbers of experiments in separate batches, and each figure shows the results of experiments in three batches.
  • a dissolution test was performed using a dissolution tester (Labfine Instrument, Korea) and a UV meter (Shimadzu, Japan) according to the dissolution test method No. 2 paddle method of the Korean Pharmacopoeia General Test Method.
  • Clopidogrel granules in the examples were tested for pH 1.2 (FIG. 12), 4.0 (FIG. 13), 6.8 (FIG. 14), water (FIG. 15), in which case the volume of the eluate was 900 ml each and the paddle rotation speed was 50. rpm and the ultraviolet wavelength were 240 nm.
  • Comparative example for the clopidogrel is Flavix Jung (Sanopia Ventis Korea, Korea).
  • aspirin granules were tested for pH 1.2 (FIG. 16), 6.0 (FIG. 17), and 6.8 (FIG. 18), in which case the volume of the eluate was 900 ml each, the paddle rotation speed was 50 rpm, and the ultraviolet wavelength was 265 nm. It was. Comparative example for the aspirin is Astrix It was a capsule (Boryeong Pharmaceuticals, Korea).
  • Comparative example of clopidogrel granules (clopidogrel hydrogen sulfate 97.875 mg, clopidogrel 75 mg) in the embodiment of the present invention is a combination formulation of Flavix A comparative example for Jung (Sanopia Ventis Korea, Korea), and aspirin granules (Aspirin 100 mg) Blood concentrations were measured using capsules (Boryeong Pharmaceutical, Korea).
  • FIG. 19 is a blood concentration graph of clopidogrel
  • FIG. 20 is a blood concentration graph of aspirin
  • FIG. 21 is a blood concentration graph of salicylic acid, a metabolite of aspirin.
  • FIGS. 19 to 21 may be summarized as follows.

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Abstract

La présente invention concerne un agent complexe de clopidogrel et d'aspirine, et plus particulièrement, un agent complexe comprenant une capsule contenant un granulé obtenu par revêtement d'une couche de clopidogrel par une couche pour prévenir la libération rapide, et un granulé d'aspirine obtenu par revêtement d'une couche d'aspirine par une couche entérique. Le contact physique entre le clopidogrel et l'aspirine peut être bloqué et le phénomène eutectique peut être fondamentalement bloqué. A court terme, une modification de la quantité, des propriétés d'élution et de la bioéquivalence de l'agent peut être empêchée et, à long terme, la stabilité de l'agent peut être garantie. En outre, les dommages à la paroi de l'estomac peuvent être empêchés par le revêtement de l'aspirine par la couche entérique.
PCT/KR2012/006316 2011-11-02 2012-08-08 Agent complexe contenant du clopidogrel et de l'aspirine Ceased WO2013065936A1 (fr)

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KR101843396B1 (ko) 2016-04-04 2018-03-29 가톨릭대학교 산학협력단 고정용량의 실로스타졸과 클로피도그렐을 포함하는 1일 1회 경구복용 이층정제 및 이의 제조방법
CN115770229A (zh) * 2022-12-13 2023-03-10 山东诺明康药物研究院有限公司 一种硫酸氯吡格雷阿司匹林片及其制备方法和应用

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JP6657420B2 (ja) * 2016-03-16 2020-03-04 コリア ユナイテッド ファーマ． インコーポレーテッド クロピドグレル及びアスピリンを含む複合製剤
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CN107669690A (zh) * 2017-10-23 2018-02-09 罗铭炽 一种含阿司匹林和氯吡格雷的片剂
CN107693524A (zh) * 2017-10-23 2018-02-16 罗铭炽 一种含阿司匹林和氯吡格雷的制备方法
UY39094A (es) * 2020-02-27 2021-07-30 Hk Inno N Corp Composición farmacéutica que comprende compuesto derivado de bencimidazol
WO2023012479A1 (fr) * 2021-08-03 2023-02-09 Liqmeds Worldwide Limited Solution pharmaceutique orale de clopidogrel
CN114209675B (zh) * 2022-01-20 2023-06-02 北京微智瑞医药科技有限公司 一种硫酸氢氯吡格雷阿司匹林微片胶囊及其制备方法

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KR101843396B1 (ko) 2016-04-04 2018-03-29 가톨릭대학교 산학협력단 고정용량의 실로스타졸과 클로피도그렐을 포함하는 1일 1회 경구복용 이층정제 및 이의 제조방법
CN115770229A (zh) * 2022-12-13 2023-03-10 山东诺明康药物研究院有限公司 一种硫酸氯吡格雷阿司匹林片及其制备方法和应用

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