WO2013065936A1 - Complex agent containing clopidogrel and aspirin - Google Patents

Complex agent containing clopidogrel and aspirin 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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Prior art keywords
aspirin
clopidogrel
acid
mixtures
group
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PCT/KR2012/006316
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French (fr)
Korean (ko)
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정원태
최연웅
남규열
박상만
하대철
도남혁
이성능
신경도
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한국유나이티드제약 주식회사
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Priority to CN201280053817.4A priority Critical patent/CN103957895A/en
Publication of WO2013065936A1 publication Critical patent/WO2013065936A1/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
    • 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.

Abstract

The present invention relates to a complex agent of clopidogrel and aspirin, and more particularly, to a complex agent including a capsule containing a granule obtained by coating a clopidogrel layer with a layer for preventing rapid release, and an aspirin granule obtained by coating an aspirin layer with a enteric layer. The physical contact between the clopidogrel and the aspirin may be blocked, and the eutectic phenomenon may be fundamentally blocked. In the short term, a change in the amount, elution properties, and bioequivalence of the agent may be prevented, and in the long term, the stability of the agent may be ensured. In addition, damage to the stomach wall may be prevented by coating the aspirin with the enteric layer.

Description

클로피도그렐 및 아스피린의 복합제제Clopidogrel with Aspirin
본 발명은 클로피도그렐과 아스피린을 포함하는 복합제제에 관한 것이다. 구체적으로, 클로피도그렐 층을 속방보호층으로 코팅한 과립과 아스피린층을 장용층으로 코팅한 아스피린 과립을 캡슐에 담은 안정하고 생체이용률이 확보된 복합제제에 관한 것이다.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.
클로피도그렐, 즉 메틸 (+)-(S)-α-(2-클로로페닐)-6,7-디히드로티에노[3,2-c]피리딘-5(4H)-아세테이트는 뇌졸중, 혈전증 및 색전증과 같은 말초 동맥 질환뿐 아니라, 뇌졸중, 혈전증, 색전증 및 심근 경색증과 같은 관상 동맥 질환의 치료에 효과적인 혈소판 응집 억제제이다. 클로피도그렐은 아데노신 디포스페이트 (ADP) 수용체에 대한 ADP 결합의 직접적인 억제 및 뒤이은 당단백질 GPIIb/IIa 복합체의 ADP-매개된 활성화의 직접적인 억제에 의하여, ADP-유도된 혈소판 응집을 억제한다. 또한, 클로피도그렐은 방출된 ADP에 의한 혈소판 활성화의 증폭을 차단함으로써 ADP를 제외한 아고니스트 (agonist)에 의해 유발된 혈소판 응집을 억제한다.Clopidogrel, ie, methyl (+)-(S) -α- (2-chlorophenyl) -6,7-dihydrothieno [3,2-c] pyridine-5 (4H) -acetate, is known to cause stroke, thrombosis and embolism In addition to peripheral arterial diseases such as, 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. Clopidogrel also inhibits platelet aggregation caused by agonists other than ADP by blocking amplification of platelet activation by released ADP.
이러한 클로피도그렐의 약리작용은 클로피도그렐이 경구 투여된 후 간에서 대사되어 형성되는 활성형 대사체에 의해 이루어진다. 이 활성형 대사체는 선택적으로 그리고 비가역적으로 혈소판에 있는 ADP 수용체를 변형시킴으로써, ADP가 ADP 수용체와 결합하는 것을 방해한다. 그러므로 클로피도그렐의 효과는 간에서 클로피도그렐을 대사시키는 효소에 크게 의존한다.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.
클로피도그렐의 대표적인 제약원료인 클로피도그렐 바이설페이트의 화학 명칭은 메틸 (+)-(S)-α-(2-클로로페닐)-6,7-디히드로티에노[3,2-c]피리딘-5(4H)-아세테이트 설페이트 (1:1)이다. 클로피도그렐 바이설페이트의 실험식은 C16H16ClNO2S·H2SO4이고, 그 분자량은 419.9이다.The chemical name for clopidogrel bisulfate, a representative pharmaceutical ingredient of clopidogrel, is methyl (+)-(S) -α- (2-chlorophenyl) -6,7-dihydrothieno [3,2-c] pyridine-5 ( 4H) -acetate sulfate (1: 1). 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.
클로피도그렐 바이설페이트는 백색 내지 회색 분말이다. 이것은 실질적으로 중성 pH의 물에서 불용성이지만, pH 1.0에서는 매우 가용성이다. 이것은 또한 메탄올에서 잘 용해되고 (freely soluble), 메틸렌 클로라이드에서 약간 용해되며, 에틸 에테르에서 실질적으로 불용성 (practically insoluble)이다.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.
클로피도그렐 바이설페이트는 급성 (recent) 심근 경색 (myocardial infarction, MI), 급성 뇌졸중 (stroke), 또는 확립된 (established) 동맥 질환 (arterial disease)과 같은 혈전증 발병 (thrombotic event)의 감소를 위해 처방되고, 새로운 (new) 허혈성 뇌졸중 (ischemic stroke), 새로운 MI, 및 그 밖의 혈관성 사망 (vascular death)의 복합된 종점 (combined end point)의 속도를 감소시킨다고 밝혀졌다. 급성 관상 동맥 증후군이 있는 환자의 경우, 클로피도그렐 바이설페이트는 심장혈관에 의한 사망, MI, 또는 뇌졸중의 복합된 종점의 속도뿐만 아니라, 심장혈관성 사망, MI, 뇌졸중, 또는 불응성 허혈 (refractory ischemia)의 복합된 종점의 속도를 감소시킨다고 밝혀졌다.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. In patients with acute coronary syndromes, 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.
또한 아세틸살리실산으로 알려져 있는 아스피린은 진통제 (경미한 통증과 동통에 대하여), 해열제 (발열에 대하여), 및 항-염증제로서 종종 사용된다. 아스피린은 또한 항응고제 (혈액을 묽게 함, blood thinning) 효과가 있고, 장기간의 낮은 투여량으로 심장 발작 (heart attack)을 예방하는데 사용된다.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.
CAS 번호 (Number): 50-78-2인 아스피린은 화학적으로 2-아세톡시벤조산으로 알려져 있다. 아스피린은 분자식이 C9H8O4이고, 분자량은 180.16이다.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.
아스피린은 무색 또는 백색의 결정 또는 백색의 결정형 분말 또는 과립이다. 아스피린은 무취 또는 약간의 신맛이 난다. 아스피린의 녹는점은 136℃이고, 끓는점은 140℃이다. 아스피린은 유리산 (free acid), 아세트아닐리드, 아미노피린, 페나존 (phenazone), 헥사민, 철 염, 페노바르비톤 나트륨, 퀴닌 염, 포타슘 및 나트륨 요오드, 및 알칼리 히드록시드, 카보네이트, 및 스테아레이트와 양립 불가능하다. 아세틸살리실산은 건조 공기에서 안정하지만, 수분과 접촉하면 점차적으로 가수분해되어 아세트산과 살리실산으로 된다. 알칼리 용액에서, 가수분해는 빨리 진행하여, 형성된 투명한 용액은 완전히 아세테이트와 살리실레이트로 구성될 수 있다. 아세틸살리실산은 암모늄 아세테이트, 또는 알칼리 금속의 아세테이트, 카보네이트, 시트레이트 또는 히드록시드 용액에서 빨리 분해된다.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. In alkaline solutions, hydrolysis proceeds rapidly, so that the clear solution formed can consist entirely of acetate and salicylate. Acetylsalicylic acid is rapidly decomposed in ammonium acetate, or an acetate, carbonate, citrate or hydroxide solution of alkali metals.
아스피린은 경미한 정도 내지 중간 정도의 통증의 치료를 위한 진통제로서, 연 조직 (soft tissue) 및 관절 염증의 치료를 위한 항-염증제로서, 및 해열제용 약물로서 처방된다. 아스피린은 일반적으로 통증과 발열이 있는 성인에서 4 시간마다 300-1000 mg의 함량으로 하루 당 최대 4 g의 함량으로 투여된다. 급성 류마티스성 다발성 관절염 (acute polyarthritis rheumatica)의 경우, 투여는 일반적으로 하루에 6회로 1 g이 제공되고 하루당 최대 8 g이 제공된다. 류마티스 관절염의 경우, 투여는 일반적으로 하루에 6회 0.5 g 내지 1 g으로 제공되고 하루당 최대 8 g이 제공된다. 일과성 허혈 발작의 예방 및 동맥 혈전증의 예방을 위하여, 투여는 일반적으로 2회 또는 3회의 투여로 하루 당 300 mg 내지 1200 mg이 투여된다.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. For acute polyarthritis rheumatica, administration is generally given 1 g six times a day and up to 8 g per day. In the case of rheumatoid arthritis, administration is generally given from 0.5 g to 1 g six times a day and up to 8 g per day. For the prevention of transient ischemic attacks and the prevention of arterial thrombosis, administration is generally administered from 300 mg to 1200 mg per day in two or three doses.
아스피린은 심장 발작, 뇌졸중, 또는 혈관이 혈액 응고물 (blood clot)에 의해 막혔을 때 발생될 수 있는 그 밖의 문제의 가능성을 줄이기 위해 사용될 수 있다. 아스피린은 위험한 혈액 응고물이 생성되는 것을 막아준다.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.
낮은-투여량으로 장-기간의 아스피린은 혈소판에서 트롬복산 A2의 생성을 비가역적으로 차단하여, 혈소판 응집에 대해 억제 효과를 생성하고, 이러한 혈액을 묽게 하는 특징이 심장 발작의 발생률을 감소시키는데 유용하다.Low-dose long-term aspirin irreversibly blocks the production of thromboxane A2 in platelets, creating an inhibitory effect on platelet aggregation, and this blood thinning feature is useful for reducing the incidence of heart attacks Do.
그런데, 아스피린은 클로피도그렐을 간에서 활성형 대사체로 변화시키는 효소를 활성화시키는 것으로 알려져 있다. 따라서, 클로피도그렐과 아스피린을 함께 투여하는 제형에 대해 많은 연구가 이루어져 왔으나, 두 약물이 직접 접촉하는 경우 공융 (eutectic)현상이 발생하는 문제가 있다. 무엇보다, 아스피린은 위장흡수가 적은 물질이어서 일정량 이상을 투여해야 하나, 아스피린 자체가 위장을 상하게 하는 성질이 있어 그 사용량에 제한이 상당하다. 이러한 문제는 클로피도그렐의 대사증대를 위해 아스피린이 먼저 용출되는 제형에서 그 문제가 더욱 심각해진다.However, 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.
즉, 비록 아스피린이 간에서의 클로피도그렐 활성형 대사체 생성을 촉진시키기는 하나, 이러한 활성형 대사체 생성은 개인차가 존재하여 약물 혈중농도에 예기치 못한 편차를 일으킬 수도 있어 늘 바람직한 것은 아니다. 구체적으로, 선방출된 아스피린이 활성화시키는 시토크롬 P450 2C19 (CYP450 2C19) 간대사효소는 그 활성형 대사체의 생성 정도에 개인차가 존재하는데, 이러한 개인차는 필연적으로 상기 활성형 대사체의 약물 혈중농도에 편차를 발생시킨다. 그리고, 이러한 편차는 제어될 수 없는 것이어서 환자에게 예측할 수 없는 영향을 미칠 수 있어 바람직하지 않은 것이다.That is, although aspirin promotes clopidogrel-activated metabolite production in the liver, such active metabolite production is not always desirable because of individual differences that can cause unexpected variations in drug blood levels. Specifically, 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.
[선행기술문헌][Preceding technical literature]
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(특허문헌 3) WO 2000/66130 A (사노피-신델라보) 2000.11.9.(Patent Document 3) WO 2000/66130 A (Sanopy-Sindelabo) 2000.11.9.
(특허문헌 4) WO 1997/29753 A (사노피 디.꼬쉬) 1997.8.21.(Patent Document 4) WO 1997/29753 A (Sanopy D. Kosch) 1997.8.21.
본 발명은 상기와 같은 문제점을 해결하기 위하여 안출된 것으로서, 클로피도그렐층을 속방보호층으로 코팅한 과립과 아스피린층을 장용층으로 코팅한 과립을 함께 캡슐에 담은 안정하고 생체이용률이 확보된 복합제제를 제공하는 것을 그 목적으로 한다.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.
본 발명의 복합제제는 상술한 바와 같은 목적을 달성하기 위하여,In order to achieve the object as described above, the combination preparation of the present invention,
(A) 부형제를 포함하는 내핵,(A) an inner core comprising an excipient,
상기 내핵의 바깥에 인접하고, 약리학적 활성성분으로서 클로피도그렐, 그의 이성질체 또는 그의 약제학적으로 허용가능한 염 및 제 1 결합제를 포함하는 클로피도그렐 외핵, 및Adjacent 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
상기 외핵의 바깥에 인접하고, 제 2 결합제 및 제 1 가소제를 포함하는 속방보호층Immediate protective layer adjacent to the outside of the outer core, comprising a second binder and a first plasticizer
을 포함하는 클로피도그렐 과립,Clopidogrel granules, including
(B) 부형제를 포함하는 내핵,(B) an inner core comprising an excipient,
상기 내핵의 바깥에 인접하고, 약리학적 활성성분으로서 아스피린 또는 그의 약제학적으로 허용가능한 염 및 제 3 결합제를 포함하는 아스피린 외핵, 및Aspirin external nucleus adjacent to the outside of the inner core and comprising as a pharmacologically active ingredient aspirin or a pharmaceutically acceptable salt thereof and a third binder, and
상기 외핵의 바깥에 인접하고, 장용성 코팅제 및 제 2 가소제를 포함하는 장용층An enteric layer adjacent to the outside of the outer core and comprising an enteric coating and a second plasticizer
을 포함하는 아스피린 과립,Aspirin granules, including
(C) 상기 클로피도그렐 과립 및 아스피린 과립을 수용하는 캡슐(C) a capsule containing the clopidogrel granules and aspirin granules
을 포함하는 것을 특징으로 한다.Characterized in that it comprises a.
또한, 상기 클로피도그렐 외핵은 제 3 가소제를 추가로 포함할 수 있다.In addition, the clopidogrel outer core may further comprise a third plasticizer.
또한, 상기 아스피린 외핵은 제 4 가소제를 추가로 포함할 수 있다.In addition, the aspirin extranucleus may further comprise a fourth plasticizer.
또한, 상기 부형제는 설탕, 전분, 미결정셀룰로오스, 락토오스, 카르나우바 왁스, 만니톨, 주석산, 자일리톨 및 그 혼합물로 이루어진 군에서 선택될 수 있다.In addition, the excipient may be selected from the group consisting of sugar, starch, microcrystalline cellulose, lactose, carnauba wax, mannitol, tartaric acid, xylitol, and mixtures thereof.
또한, 상기 클로피도그렐의 약제학적으로 허용가능한 염은 클로피도그렐의 황산수소염, 레지네이트, 캄실산염, 베실산염, 나파디실레이트일수화물염, 염산염 및 그 혼합물로 이루어진 군에서 선택될 수 있다.In addition, 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.
또한, 상기 제 1 결합제, 제 2 결합제 및 제 3 결합제는 각각 독립적으로 치환 또는 비치환된 알킬셀룰로오스 또는 그의 염, 폴리비닐유도체, 폴리알킬렌글리콜, 폴리메타크릴산 및 그 혼합물로 이루어진 군에서 선택될 수 있다.In addition, the 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.
또한, 상기 치환 또는 비치환된 알킬셀룰로오스 또는 그의 염은 메틸셀룰로오스, 에틸셀룰로오스, 히드록시에틸셀룰로오스, 메틸히드록시에틸셀룰로오스, 히드록시프로필셀룰로오스, 히드록시프로필메틸셀룰로오스, 카르복시메틸셀룰로오스나트륨 및 그 혼합물로 이루어진 군에서 선택될 수 있다.In addition, the 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.
또한, 상기 폴리비닐유도체는 폴리비닐피롤리돈, 폴리비닐알코올 및 그 혼합물로 이루어진 군에서 선택될 수 있다.In addition, the polyvinyl derivative may be selected from the group consisting of polyvinylpyrrolidone, polyvinyl alcohol and mixtures thereof.
또한, 상기 폴리알킬렌글리콜은 폴리에틸렌글리콜, 폴리프로필렌글리콜 및 그 혼합물로 이루어진 군에서 선택될 수 있다.In addition, the polyalkylene glycol may be selected from the group consisting of polyethylene glycol, polypropylene glycol and mixtures thereof.
또한, 상기 폴리메타크릴산은 폴리(부틸메타크릴산-co-(2-디메틸아미노에틸)메타크릴산-co-메틸메타크릴산), 폴리(에틸아크릴산-co-메틸메타크릴산), 폴리(에틸아크릴산-co-메틸메타크릴산-co-트리메틸아미노에틸메타크릴산 클로라이드) 및 그 혼합물로 이루어진 군에서 선택될 수 있다.Further, 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.
또한, 상기 제 1 가소제, 제 2 가소제, 제 3 가소제 및 제 4 가소제는 각각 독립적으로 글리콜, 에스테르, 오일, 글리세린, 글리세린유도체 및 그 혼합물로 이루어진 군에서 선택될 수 있다.In addition, the 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.
또한, 상기 글리콜은 프로필렌글리콜, 폴리에틸렌글리콜 및 그 혼합물로 이루어진 군에서 선택될 수 있다.In addition, the glycol may be selected from the group consisting of propylene glycol, polyethylene glycol and mixtures thereof.
또한, 상기 에스테르는 프탈산디에틸, 프탈산디부틸, 디부틸세바케이트, 트리에틸시트레이트, 아세틸트리에틸시트레이트, 아세틸트리부틸시트레이트, 트리아세틴 및 그 혼합물로 이루어진 군에서 선택될 수 있다.In addition, the 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.
또한, 상기 오일은 피마자유, 코코넛유 및 그 혼합물로 이루어진 군에서 선택될 수 있다.In addition, the oil may be selected from the group consisting of castor oil, coconut oil and mixtures thereof.
또한, 상기 글리세린 및 글리세린유도체는 글리세린, 모노스테아린산글리세린 및 그 혼합물로 이루어진 군에서 선택될 수 있다.In addition, the glycerin and glycerin derivative may be selected from the group consisting of glycerin, glycerin monostearate and mixtures thereof.
또한, 상기 장용성 코팅제는 쉘락, 히드록시프로필메틸셀룰로오스아세테이트숙시네이트, 히드록시프로필메틸셀룰로오스프탈레이트, 셀룰로오스아세테이트프탈레이트, 셀룰로오스아세테이트, 폴리비닐알코올프탈레이트, 폴리(메타크릴산-co-메틸메타크릴산), 폴리(메틸아크릴산-co-메틸메타크릴산-co-메타크릴산), 폴리(메타크릴산-co-에틸아크릴산) 및 그 혼합물로 이루어진 군에서 선택될 수 있다.In addition, 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.
또한, 상기 클로피도그렐 외핵, 아스피린 외핵, 속방보호층 또는 장용층에는 희석제, 활택제, 안정화제, 필름코팅제 및 그 혼합물로 이루어진 군에서 선택된 첨가제를 추가로 포함할 수 있다.In addition, the 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.
또한, 상기 클로피도그렐 100 중량부에 대해 아스피린은 10 내지 1000 중량부일 수 있다.In addition, aspirin may be 10 to 1000 parts by weight based on 100 parts by weight of the clopidogrel.
또한, 상기 캡슐은 경질 캡슐일 수 있다.In addition, the capsule may be a hard capsule.
한편, 본 명세서에 사용된 “속방보호층”이라는 용어는 클로피도그렐 외핵의 외부 표면에 도포되어 클로피도그렐이 아스피린과 직접적으로 접촉하는 것을 차단함 (보호층)과 동시에 크로피도그렐이 위에서 먼저 방출 (속방)될 수 있도록 도와주는 역할을 수행하는 층을 의미한다.On the other hand, the term "immediately protective layer" as used herein 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.
본 발명의 복합제제는 클로피도그렐과 아스피린을 하나의 캡슐에 충진하되, 클로피도그렐은 속방성 과립으로, 아스피린을 장용성 과립으로 하여 충진하여 주성분인 클로피도그렐과 아스피린이 물리적으로 직접 접촉하지 못하도록 설계함으로써, 두 성분의 공융현상을 원천적으로 차단하였다는 데 가장 큰 특징이 있다. 이처럼 공융현상을 배제하여 각 성분의 물리화학적 성질의 변화를 방지함으로써, 단기적으로 제제의 함량, 용출특성, 생물학적 동등성 (bioequivalence)의 변화를 방지하고, 장기적으로 제제의 안정성을 제고하는 효과가 있다.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.
뿐만 아니라, 본 발명의 복합제제는 아스피린이 위벽을 자극하여 손상을 일으키는 문제점의 예방을 위해, 아스피린은 장에서만 용출되고 위에서는 용출되지 않도록 아스피린을 장용층으로 코팅하였다. 따라서, 본 발명의 복합제제를 경구 투여하면 클로피도그렐이 위에서 먼저 용출되고, 아스피린은 장에서 나중에 용출됨으로써 위벽 손상을 예방하는 효과가 있다.In addition, the combination preparation of the present invention coated aspirin with an enteric layer so that aspirin elutes only in the intestine and does not elute in the stomach, in order to prevent the problem of aspirin irritating the stomach wall and causing damage. Therefore, oral administration of the combination preparation of the present invention, clopidogrel is eluted from the stomach first, aspirin is eluted later in the intestine has the effect of preventing gastric wall damage.
마지막으로 본 발명의 복합제제는 클로피도그렐과 아스피린을 동시에 또는 시간차를 두고 각각 복용하는 경우에 비해 복용의 편의성과 순응도를 증대시킬 수 있음은 물론이며, 상호보완적인 두 약물의 약리작용으로 인해 종래 제제에 비해 적은 용량으로도 동일한 결과를 나타낼 수 있고, 약리성분에 의한 부작용과 제조비용을 절감하는 장점이 있다.Finally, 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.
도 1은 본 발명의 복합제제의 구조에 대한 개략도이다.1 is a schematic diagram of the structure of the co-formulation of the present invention.
도 2는 클로피도그렐 황산수소염의 시차주사열량계 그래프이다.2 is a differential scanning calorimeter graph of clopidogrel hydrogen sulfate.
도 3은 아스피린의 시차주사열량계 그래프이다.3 is a differential scanning calorimeter graph of aspirin.
도 4는 클로피도그렐 황산수소염과 아스피린 혼합물의 시차주사열량계 그래프이다.4 is a differential scanning calorimetry graph of clopidogrel hydrogen sulfate and aspirin mixture.
도 5는 6 개월 가속시험에서 클로피도그렐의 함량 변화 그래프이다.Figure 5 is a graph of the change in the content of clopidogrel in 6 months accelerated test.
도 6은 6 개월 가속시험에서 아스피린의 함량 변화 그래프이다.Figure 6 is a graph of the change in the content of aspirin in the 6 month accelerated test.
도 7은 6 개월 가속시험에서 클로피도그렐의 용출율 변화 그래프이다.7 is a graph of change in dissolution rate of clopidogrel in the 6 month accelerated test.
도 8은 6 개월 가속시험에서 0.1 N HCl 중의 아스피린의 용출율 변화 그래프이다.8 is a graph showing the change in dissolution rate of aspirin in 0.1 N HCl in a 6 month accelerated test.
도 9는 6 개월 가속시험에서 pH 6.8 중의 아스피린의 용출율 변화 그래프이다.9 is a graph showing the change in dissolution rate of aspirin in pH 6.8 in the 6 month accelerated test.
도 10은 6 개월 가속시험에서 클로피도그렐의 총 유연물질 함량 변화 그래프이다.FIG. 10 is a graph showing the change in total lead content of clopidogrel in the 6 month accelerated test.
도 11은 6 개월 가속시험에서 아스피린의 총 유연물질 함량 변화 그래프이다.Figure 11 is a graph of the total amount of analogues of aspirin in 6 months accelerated test.
도 12는 클로피도그렐 과립과 플라빅스　정에 대한 pH 1.2에서의 비교용출 그래프이다.Figure 12 Clopidogrel granules and flavix 　 Comparative elution graph at pH 1.2 against tablets.
도 13은 클로피도그렐 과립과 플라빅스　정에 대한 pH 4.0에서의 비교용출 그래프이다.FIG. 13 shows clopidogrel granules and flavix 　 Comparative elution graph at pH 4.0 for tablets.
도 14는 클로피도그렐 과립과 플라빅스　정에 대한 pH 6.8에서의 비교용출 그래프이다.Figure 14 Clopidogrel Granules and Plavix 　 Comparative elution graph at pH 6.8 for tablets.
도 15는 클로피도그렐 과립과 플라빅스　정에 대한 물에서의 비교용출 그래프이다.Figure 15 Clopidogrel granules and flavix 　 A graph of comparative elution in water against tablets.
도 16은 아스피린 과립과 아스트릭스　캡슐에 대한 pH 1.2에서의 비교용출 그래프이다.16 is aspirin granules and astrix 　 Comparative elution graph at pH 1.2 for capsules.
도 17은 아스피린 과립과 아스트릭스　캡슐에 대한 pH 6.0에서의 비교용출 그래프이다.17 is aspirin granules and astrix 　 Comparative elution graph at pH 6.0 for capsules.
도 18은 아스피린 과립과 아스트릭스　캡슐에 대한 pH 6.8에서의 비교용출 그래프이다.18 is aspirin granules and astrix 　 Comparative elution graph at pH 6.8 for capsules.
도 19는 클로피도그렐의 혈중농도 그래프이다.19 is a graph of blood concentration of clopidogrel.
도 20은 아스피린의 혈중농도 그래프이다.20 is a graph of blood concentration of aspirin.
도 21은 살리실산의 혈중농도 그래프이다.21 is a graph of blood concentration of salicylic acid.
이하, 본 발명의 바람직한 실시예에 대하여 상세히 설명한다. 또한, 하기의 설명에서는 구체적인 구성요소 등과 같은 많은 특정사항들이 설명되어 있는데, 이는 본 발명의 보다 전반적인 이해를 돕기 위해서 제공된 것일 뿐 이러한 특정 사항들 없이도 본 발명이 실시될 수 있음은 이 기술분야에서 통상의 지식을 가진 자에게는 자명하다 할 것이다. 그리고, 본 발명을 설명함에 있어서, 관련된 공지 기능 혹은 구성에 대한 구체적인 설명이 본 발명의 요지를 불필요하게 흐릴 수 있다고 판단되는 경우 그 상세한 설명을 생략한다.Hereinafter, preferred embodiments of the present invention will be described in detail. In addition, many specific details such as specific components are described in the following description, which is provided to help a more general understanding of the present invention, and the present invention may be practiced without these specific details. It is self-evident to those who have knowledge of the world. In describing the present invention, when it is determined that a detailed description of a related known function or configuration may unnecessarily obscure the subject matter of the present invention, the detailed description thereof will be omitted.
본 발명의 복합제제는 도 1에 도시된 바와 같이 캡슐 안에 클로피도그렐 과립과 아스피린 과립을 포함하고 있으며, 상기 클로피도그렐 과립은 부형제를 포함하는 내핵, 상기 내핵의 바깥에 인접하고, 약리학적 활성성분으로서 클로피도그렐, 그의 이성질체 또는 그의 약제학적으로 허용가능한 염 및 제 1 결합제를 포함하는 클로피도그렐 외핵, 및 상기 외핵의 바깥에 인접하고, 제 2 결합제 및 제 1 가소제를 포함하는 속방보호층을 포함한다. 그리고, 아스피린 과립은 부형제를 포함하는 내핵, 상기 내핵의 바깥에 인접하고, 약리학적 활성성분으로서 아스피린 또는 그의 약제학적으로 허용가능한 염 및 제 3 결합제를 포함하는 아스피린 외핵, 및 상기 외핵의 바깥에 인접하고, 장용성 코팅제 및 제 2 가소제를 포함하는 장용층을 포함한다.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. In addition, 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. And an enteric layer comprising an enteric coating and a second plasticizer.
이러한 본 발명의 복합제제는 먼저 위에서 클로피도그렐 과립이 용출되고, 아스피린 과립은 나중에 장에서 용출된다. 따라서, 클로피도그렐과 아스피린의 상호보완적인 약리효과를 발현시킬 수 있으면서도, 아스피린에 의한 위벽 손상을 방지할 수 있다. 나아가, 클로피도그렐과 아스피린이 직접 접촉하는 것을 차단함으로써 공융현상을 방지하여 함량이나 용출특성의 변화를 막고 약제의 안정성을 제고할 수 있다.Such a co-formulation of the present invention is first eluted clopidogrel granules in the stomach, aspirin granules are later eluted in the intestine. Thus, while complementary pharmacological effects of clopidogrel and aspirin can be expressed, gastric wall damage caused by aspirin can be prevented. Furthermore, by blocking the direct contact between clopidogrel and aspirin, the eutectic can be prevented, thereby preventing changes in content or dissolution characteristics and improving the stability of the drug.
본 발명의 복합제제에서 상기 클로피도그렐 외핵은 제 3 가소제를, 그리고 상기 아스피린 외핵은 제 4 가소제를 추가로 포함할 수 있다. 이러한 가소제는 강직 (剛直)한 고분자에 소성 (塑性)을 부여하여 가공성을 개량하며, 정제 및 과립의 코팅 시 코팅피막의 유연성을 보조하는 역할을 한다.In the co-formulation of the present invention, the clopidogrel outer core may further include a third plasticizer, and the aspirin outer core may further include a fourth plasticizer. These plasticizers impart plasticity to rigid polymers to improve processability and assist in flexibility of the coating film when coating tablets and granules.
또한, 상기 부형제는 설탕, 전분, 미결정셀룰로오스, 락토오스, 카르나우바 왁스, 만니톨, 주석산, 자일리톨 및 그 혼합물로 이루어진 군에서 선택될 수 있으며, 특히 설탕이 바람직하다.In addition, 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.
그리고, 상기 클로피도그렐의 약제학적으로 허용가능한 염은 클로피도그렐의 황산수소염, 레지네이트, 캄실산염, 베실산염, 나파디실레이트일수화물염, 염산염 및 그 혼합물로 이루어진 군에서 선택될 수 있으며, 특히 황산수소염과 베실산염이 바람직하다.In addition, 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.
또한, 상기 제 1 결합제, 제 2 결합제 및 제 3 결합제는 각각 독립적으로 치환 또는 비치환된 알킬셀룰로오스 또는 그의 염, 폴리비닐유도체, 폴리알킬렌글리콜, 폴리메타크릴산 및 그 혼합물로 이루어진 군에서 선택될 수 있는데, 이 중 상기 치환 또는 비치환된 알킬셀룰로오스 또는 그의 염은 메틸셀룰로오스, 에틸셀룰로오스, 히드록시에틸셀룰로오스, 메틸히드록시에틸셀룰로오스, 히드록시프로필셀룰로오스, 히드록시프로필메틸셀룰로오스, 카르복시메틸셀룰로오스나트륨, 그의 염 및 그 혼합물로 이루어진 군에서 선택될 수 있으며, 특히 히드록시프로필메틸셀룰로오스가 바람직하다.In addition, the 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. Among these, 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.
그리고, 상기 폴리비닐유도체는 폴리비닐피롤리돈, 폴리비닐알코올 및 그 혼합물로 이루어진 군에서 선택될 수 있고, 상기 폴리알킬렌글리콜은 폴리에틸렌글리콜, 폴리프로필렌글리콜 및 그 혼합물로 이루어진 군에서 선택될 수 있다.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.
또한, 상기 폴리메타크릴산은 폴리(부틸메타크릴산-co-(2-디메틸아미노에틸)메타크릴산-co-메틸메타크릴산), 폴리(에틸아크릴산-co-메틸메타크릴산), 폴리(에틸아크릴산-co-메틸메타크릴산-co-트리메틸아미노에틸메타크릴산 클로라이드) 및 그 혼합물로 이루어진 군에서 선택될 수 있다.Further, 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.
상기 폴리메타크릴산 중 폴리(부틸메타크릴산-co-(2-디메틸아미노에틸)메타크릴산-co-메틸메타크릴산)은 Evonik Degussa(독일)의 Eudragit E 100, Eudragit E 12.5, 또는 Eudragit E PO와 같은 폴리(부틸메타크릴산-co-(2-디메틸아미노에틸)메타크릴산-co-메틸메타크릴산) 1:2:1이 더욱 바람직하다.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.
그리고, 상기 폴리(에틸아크릴산-co-메틸메타크릴산)은 Evonik Degussa (독일)의 Eudragit NE 30D, Eudragit NE 40D, Eudragit NM 30D와 같은 폴리(에틸아크릴산-co-메틸메타크릴산) 2:1이 더욱 바람직하다.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.
그리고, 상기 폴리(에틸아크릴산-co-메틸메타크릴산-co-트리메틸아미노에틸메타크릴산 클로라이드)는 Evonik Degussa (독일)의 Eudragit RL 100, Eudragit RL PO, Eudragit RL 30D, Eudragit RL 12.5와 같은 상기 폴리(에틸아크릴산-co-메틸메타크릴산-co-트리메틸아미노에틸메타크릴산 클로라이드) 1:2:0.2나 Eudragit RS 100, Eudragit RS PO, Eudragit RS 30D, Eudragit RS 12.5와 같은 상기 폴리(에틸아크릴산-co-메틸메타크릴산-co-트리메틸아미노에틸메타크릴산 클로라이드) 1:2:0.1이 더욱 바람직하다.In addition, the poly (ethylacrylic acid-co-methylmethacrylic acid-co-trimethylaminoethylmethacrylic chloride) may be used as Edranik RL 100, Eudragit RL PO, Eudragit RL 30D, Eudragit RL 12.5 of Evonik Degussa (Germany). Poly (ethylacrylic acid-co-methylmethacrylic acid-co-trimethylaminoethylmethacrylate chloride) 1: 2: 0.2 or Eudragit RS 100, Eudragit RS PO, Eudragit RS 30D, Eudragit RS 12.5 -co-methylmethacrylic acid-co-trimethylaminoethylmethacrylic chloride) 1: 2: 0.1 is more preferable.
또한, 상기 제 1 가소제, 제 2 가소제, 제 3 가소제 및 제 4 가소제는 각각 독립적으로 글리콜, 에스테르, 오일, 글리세린, 글리세린유도체 및 그 혼합물로 이루어진 군에서 선택될 수 있는데, 이 중에서 글리콜은 프로필렌글리콜, 폴리에틸렌글리콜 및 그 혼합물로 이루어진 군에서 선택될 수 있고, 에스테르는 프탈산디에틸, 프탈산디부틸, 디부틸세바케이트, 트리에틸시트레이트, 아세틸트리에틸시트레이트, 아세틸트리부틸시트레이트, 트리아세틴 및 그 혼합물로 이루어진 군에서 선택될 수 있다.In addition, the 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.
그리고, 상기 오일은 피마자유, 코코넛유 및 그 혼합물로 이루어진 군에서 선택될 수 있고, 글리세린 및 글리세린유도체는 글리세린, 모노스테아린산글리세린 및 그 혼합물로 이루어진 군에서 선택될 수 있다.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.
한편, 상기 장용성 코팅제는 쉘락, 히드록시프로필메틸셀룰로오스아세테이트숙시네이트, 히드록시프로필메틸셀룰로오스프탈레이트, 셀룰로오스아세테이트프탈레이트, 셀룰로오스아세테이트, 폴리비닐알코올프탈레이트, 폴리(메타크릴산-co-메틸메타크릴산), 폴리(메틸아크릴산-co-메틸메타크릴산-co-메타크릴산), 폴리(메타크릴산-co-에틸아크릴산) 및 그 혼합물로 이루어진 군에서 선택될 수 있다.On the other hand, 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.
이 중에서 폴리(메타크릴산-co-메틸메타크릴산)은 Evonik Degussa (독일)의 Eudragit L 100, Eudragit L 12.5, Eudragit L 100 P와 같은 폴리(메타크릴산-co-메틸메타크릴산) 1:1이나, Eudragit S 100, Eudragit S 12.5, Eudragit S 100 P와 같은 폴리(메타크릴산-co-메틸메타크릴산) 1:2가 더욱 바람직하다.Among them, 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.
그리고, 폴리(메틸아크릴산-co-메틸메타크릴산-co-메타크릴산)은 Evonik Degussa (독일)의 Eudragit FS 30D와 같은 폴리(메틸아크릴산-co-메틸메타크릴산-co-메타크릴산) 7:3:1이 더욱 바람직하다.And 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.
마지막으로, 폴리(메타크릴산-co-에틸아크릴산)은 Evonik Degussa (독일)의 Eudragit L 30 D-55, Eudragit L 100-55와 같은 폴리(메타크릴산-co-에틸아크릴산) 1:1이 더욱 바람직하다.Finally, 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.
또한, 상기 클로피도그렐 외핵, 아스피린 외핵, 속방보호층 또는 장용층에는 희석제, 활택제, 안정화제, 필름코팅제 및 그 혼합물로 이루어진 군에서 선택된 첨가제를 추가로 포함할 수 있다.In addition, the 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.
상기 희석제는 탄산칼슘, 인산칼슘, 셀룰로오스, 덱스트린, 덱스트로스, 에틸셀룰로오스, 과당, 글리세릴팔미토스테아레이트, 말토스, 수크로스, 전분, 미세결정성셀룰로오스, 유당, 포도당, 만니톨, 알기네이트, 알칼리토금속류염, 클레이, 폴리에틸렌글리콜, 디칼슘포스페이트 및 그 혼합물로 이루어진 군에서 선택될 수 있다.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.
상기 활택제는 탈크, 스테아린산 및 그 염류, 라우릴황산나트륨, 수소화식물성오일, 나트륨벤조에이트, 스테아릴푸마르산나트륨, 글리세릴모노스테아레이트, 폴리에틸렌글리콜 및 그 혼합물로 이루어진 군에서 선택될 수 있다.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.
상기 안정화제는 부틸레이티드 히드록시 톨루엔 (BHT), 부틸레이티드 히드록시 아니솔 (BHA), 아스코르빈산, 토코페롤, 에데트산 (EDTA) 및 그 혼합물로 이루어진 군에서 선택될 수 있다.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.
상기 필름코팅제는 젤라틴, 메틸셀룰로오스, 히드록시프로필셀룰로오스, 히드록시프로필메틸셀룰로오스, 폴리에틸렌글리콜, 쉘락, 에틸셀룰로오스, 메틸히드록시에틸셀룰로오스, 히드록시에틸셀룰로오스, 카르복시메틸셀룰로오스나트륨, 폴리비닐알코올, 폴리비닐피롤리돈, 비닐피롤리돈과 초산비닐의 중합체, 아크릴산에틸ㆍ메타크릴산메틸ㆍ메타크릴산 염화트리메틸암모늄에틸공중합체 (예컨대, 상품명 Eudragit RS 또는 RL, Evonik Degussa), 메타크릴산메틸ㆍ아크릴산에틸 공중합체 (예컨대, 상품명 Eudragit NE30D, Evonik Degussa), 폴리비닐아세틸디메틸아미노아세테이트 및 그 혼합물로 이루어진 군에서 선택될 수 있다.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.
본 발명의 복합제제에서 상기 클로피도그렐 외핵, 속방보호층 또는 클로피도그렐 외핵 및 속방보호층은 속방출물질을 추가로 포함하여 방출속도를 증가시킬 수 있으며, 상기 속방출물질은 붕해제, 발포제, 완충제 및 그 혼합물 중에서 선택될 수 있다.In the co-formulation of the present invention, 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.
상기 붕해제는 전분글리콜산나트륨, 옥수수전분, 감자전분 또는 전젤라틴화전분 등의 전분 또는 변성전분과, 벤토나이트, 몬모릴로나이트, 비검 (veegum) 등의 클레이와, 미세결정성셀룰로오스, 히드록시프로필셀룰로오스 또는 카르복시메틸셀룰로오스 등의 셀룰로오스류와, 알긴산나트륨 또는 알긴산 등의 알긴산류와, 크로스카멜로스 (croscarmellose)나트륨 등의 가교 셀룰로오스류와, 구아검, 잔탄검 등의 검류와, 가교 폴리비닐피롤리돈 (crospovidone) 및 그 혼합물로 이루어진 군에서 선택될 수 있다.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.
상기 발포제는 탄산포함무기물 및 유기산을 포함할 수 있다.The blowing agent may include a carbonic acid-containing inorganic material and an organic acid.
상기 탄산포함무기물은 탄산수소나트륨, 탄산나트륨, 탄산칼슘, 탄산칼륨, 탄산마그네슘, 탄산수소칼슘, 탄산수소칼륨 및 그 혼합물로 이루어진 군에서 선택될 수 있다.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.
상기 유기산은 구연산, 염산, 젖산, 인산, 프로피온산, 황산, 주석산, 푸마르산, 말산 및 그 혼합물로 이루어진 군에서 선택될 수 있다.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.
상기 완충제는 탄산칼슘, 인산이수소나트륨, 인산일수소나트륨, 글루타민산나트륨, 구연산칼륨, 탄산수소나트륨, 구연산나트륨, 수산화나트륨, 인산칼슘, 인산수소칼슘, 또는 다양한 염 및 그 혼합물로 이루어진 군에서 선택될 수 있다.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.
또한, 상기 클로피도그렐 100 중량부에 대해 아스피린은 10 내지 1000 중량부일 수 있으며, 상기 캡슐은 경질 캡슐일 수 있다.In addition, 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.
이하, 본 발명의 실시예에 대하여 설명한다.EMBODIMENT OF THE INVENTION Hereinafter, the Example of this invention is described.
실시예EXAMPLE
비교예 : 공융확인시험Comparative Example: Eutectic Confirmation Test
클로피도그렐 황산수소염 (한국유나이티드제약, 한국) 2 mg, 아스피린 (로디아, 태국) 2 mg, 및 상기 두 물질의 1 : 1 혼합물 2 mg 각각에 대하여, 시차주사열량계 (TA Instrument, 미국)를 이용하여 융점을 관찰하였다. 온도범위는 50 내지 250 ℃, 승온속도는 10 ℃/분이었다. 도 2는 클로피도그렐에 대한 시차주사열량계 그래프이고, 도 3은 아스피린에 대한 그래프, 그리고 도 4는 두 물질의 혼합물에 대한 그래프이다. 도 2 내지 도 4에 따르면 클로피도그렐 황산수소염의 융점은 178.50 ℃이고, 아스피린의 융점은 142.83 ℃이나, 그 혼합물에서는 피크가 합쳐지면서 융점이 128.41 ℃까지 감소하였다. 따라서, 두 약리활성물질은 공융이 발생함을 확인할 수 있으며, 직접 접촉을 차단할 수 있는 제형이 필요함을 알 수 있다.Melting point using a differential scanning calorimeter (TA Instrument, USA) for 2 mg of clopidogrel hydrogen sulfate (Korea United Pharmaceutical, Korea), 2 mg of aspirin (Rhodia, Thailand), and 2 mg of a 1: 1 mixture of the two substances Was observed. The temperature range was 50-250 degreeC, and the temperature increase rate was 10 degreeC / min. FIG. 2 is a differential scanning calorimetry graph for clopidogrel, FIG. 3 is a graph for aspirin, and FIG. 4 is a graph for a mixture of two substances. 2 to 4, the melting point of clopidogrel hydrogen sulfate is 178.50 ° C., and 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.
실시예 : 복합제제Example: Combination Formulation
염화메틸렌 1000 g 및 에탄올 500 g의 혼합용매에 클로피도그렐 황산수소염 (한국유나이티드제약, 한국) 97.875 g 및 히드록시프로필메틸셀룰로오스 (Shin-Etsu, 일본) 40 g을 용해시킨 후, 내핵에 해당되는 평균입경 600 내지 710 μm의 구형 백당 (IPS, 이탈리아) 과립들 92.125 g에 유동층코팅기 (Glatt GmbH Process Technology, 독일)로 상기 혼합물을 분무하여 클로피도그렐 외핵을 형성하였다. 이어서, 염화메틸렌 300 g 및 에탄올 300 g의 혼합용매에 히드록시프로필메틸셀룰로오스 (Shin-Etsu, 일본) 9.5 g 및 폴리에틸렌글리콜 (Sanyo chemical industry, 일본) 0.5 g을 용해시킨 후, 상기 클로피도그렐 외핵에 분무하여 속방보호층을 형성함으로써, 클로피도그렐 과립들을 제조하였다.Dissolve 97.875 g of Clopidogrel Hydrogen Sulfate (Korea United Pharmaceuticals, Korea) and 40 g of hydroxypropylmethylcellulose (Shin-Etsu, Japan) in a mixed solvent of 1000 g of methylene chloride and 500 g of ethanol. 92.125 g of 600-710 μm spherical white sugar (IPS, Italy) granules were sprayed with a fluid bed coater (Glatt GmbH Process Technology, Germany) to form clopidogrel outer cores. Subsequently, 9.5 g of hydroxypropylmethylcellulose (Shin-Etsu, Japan) and 0.5 g of polyethylene glycol (Sanyo chemical industry, Japan) were dissolved in a mixed solvent of 300 g of methylene chloride and 300 g of ethanol, and then sprayed into the clopidogrel outer core. By forming an immediate release protective layer, clopidogrel granules were prepared.
이와 별도로, 염화메틸렌 600 g 및 에탄올 300 g의 혼합용매에 아스피린 (Rhodia, 태국) 100 g 및 히드록시프로필메틸셀룰로오스 (Shin-Etsu, 일본) 5.0 g을 용해시킨 후, 내핵에 해당되는 평균입경 600 내지 710 μm의 구형 백당 (IPS, 이탈리아) 과립들 30 g에 유동층코팅기 (Glatt GmbH Process Technology, 독일)로 상기 혼합물을 분무하여 아스피린 외핵을 형성하였다. 이어서, 염화메틸렌 250 g 및 에탄올 250 g의 혼합용매에 히드록시프로필메틸셀룰로오스 프탈레이트 (Shin-Etsu, 일본) 9.5 g 및 트리에틸시트레이트 (Morimurabros.INC, 일본) 0.5 g을 용해시킨 후, 상기 아스피린 외핵에 분무하여 장용층을 형성함으로써, 아스피린 과립들을 제조하였다.Separately, 100 g of aspirin (Rhodia, Thailand) and 5.0 g of hydroxypropylmethylcellulose (Shin-Etsu, Japan) were dissolved in a mixed solvent of 600 g of methylene chloride and 300 g of ethanol, followed by an average particle diameter of 600 corresponding to the inner core. 30 g of spherical white sugar (IPS, Italy) granules from 710 μm were sprayed with a fluidized bed coater (Glatt GmbH Process Technology, Germany) to form the aspirin exonucleus. Subsequently, 9.5 g of hydroxypropylmethylcellulose phthalate (Shin-Etsu, Japan) and 0.5 g of triethyl citrate (Morimurabros.INC, Japan) were dissolved in a mixed solvent of 250 g of methylene chloride and 250 g of ethanol. Aspirin granules were prepared by spraying the outer core to form an enteric layer.
상기 제조된 클로피도그렐 과립들 240 mg 및 아스피린 과립들 145 mg을 경질 캡슐에 담아 본 발명의 복합제제를 제조하였다.240 mg of clopidogrel granules prepared above and 145 mg of aspirin granules were placed in a hard capsule to prepare a composite formulation of the present invention.
시험예 1: 안정성 평가Test Example 1: Evaluation of Stability
상기 실시예에 의해 제조된 본 발명의 복합제제에 대해 6 개월 기간의 가속시험 (온도 40± 2℃, 상대습도 75± 5%)을 수행하여 안정성을 평가하였으며, 평가결과를 도 5 내지 도 11에 도시하였다. 도 5 및 도 6은 2 개월 간격으로 각각 클로피도그렐과 아스피린의 함량변화를 관찰한 결과이며, 6 개월 경과 후에도 함량변화가 1 % 미만에서 유지됨을 확인할 수 있다.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%.
도 7은 2 개월 간격으로 클로피도그렐의 용출율 변화를 관찰한 결과이고, 도 8은 0.1N HCl 용액에서, 그리고 도 9는 pH 6.8에서 아스피린의 용출율 변화를 관찰한 결과이며, 6 개월 경과 후에도 유의한 용출율 변화가 관찰되지 않았다.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, and FIG. 9 at pH 6.8. No change was observed.
도 10은 2 개월 간격으로 클로피도그렐의 유연물질 함량변화를, 그리고 도 11은 아스피린의 유연물질 함량변화를 관찰한 결과이며, 마찬가지로 6 개월 경과 후에도 유의한 함량변화를 관찰할 수 없었다.FIG. 10 shows the change in the amount of analogues of clopidogrel at two month intervals, and FIG. 11 shows the change in the amount of analogues of aspirin. Similarly, no significant changes were observed after 6 months.
상기 도 5 내지 도 11의 안정성 검토 결과 본 발명의 복합제제는 요구되는 안정성 기준을 충족시키는 것으로 확인되었으며, 이는 종래 클로피도그렐과 아스피린의 직접 접촉에 의한 공융현상을 차단했기 때문으로 판단된다.As a result of the stability review of FIGS. 5 to 11, it was confirmed that the complex formulation of the present invention satisfies the required stability criteria, which is because the block of eutectic by direct contact between clopidogrel and aspirin is blocked.
도 5 내지 도 11의 그래프에 기재된 CPCS001, CPCS002 및 CPCS003은 각각 별도의 배치 (batch)로 실험한 것의 배치 번호로서, 각 도면이 3개의 배치에서 실험한 결과를 나타내고 있다CPCS001, 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.
시험예 2: 비교용출시험Test Example 2: Comparative Dissolution Test
용출시험기 (Labfine Instrument, 한국) 및 자외선측정기 (Shimadzu, 일본)를 이용하여 대한약전 일반시험법 중 용출시험법 제 2 법 패들법에 따라 비교용출시험을 행하였다. 실시예 중 클로피도그렐 과립은 pH 1.2 (도 12), 4.0 (도 13), 6.8 (도 14), 물 (도 15)에 대해 시험하였고, 이 경우 용출액의 부피는 각 900 ml, 패들회전속도는 50 rpm, 자외선 파장은 240 nm이었다. 상기 클로피도그렐에 대한 비교예는 플라빅스　정 (사노피아벤티스코리아, 한국)이었다.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).
그리고, 아스피린 과립은 pH 1.2 (도 16), 6.0 (도 17), 6.8 (도 18)에 대해 시험하였고, 이 경우 용출액의 부피는 각 900 ml, 패들회전속도는 50 rpm, 자외선 파장은 265 nm이었다. 상기 아스피린에 대한 비교예는 아스트릭스　캡슐 (보령제약, 한국)이었다.In addition, 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).
상기 도 12 내지 도 18로부터 본 발명의 복합제제는 종래 단일제제에 필적하는 용출특성을 나타냄을 확인할 수 있다.12 to 18 it can be seen that the composite formulation of the present invention exhibits dissolution characteristics comparable to the conventional single formulation.
시험예 3: 임상시험Test Example 3: Clinical Trial
본 발명의 복합제제인 실시예 중 클로피도그렐 과립 (클로피도그렐 황산수소염 97.875 mg, 클로피도그렐 75 mg)에 대한 비교예는 플라빅스　정 (사노피아벤티스코리아, 한국), 그리고 아스피린 과립 (아스피린 100 mg)에 대한 비교예는 아스트릭스　캡슐 (보령제약, 한국)로 하여 혈중농도를 측정하였다.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).
구체적으로, 실시예군 및 비교예군 각 33 명씩을 선발하여 1 일째 1 회 각 2 캡슐 (또는 정)씩 복용하고, 정해진 주기에 따라 채혈한 후, 실시예군과 비교예군을 바꾸어 14 일의 휴약기 후 15 일째 다시 1 회 각 2 캡슐 (또는 정)을 복용하고 동일한 주기에 따라 채혈한 결과를 평균 (최초 66 명의 인원 중 중도탈락자 5 명을 제외한 61 명에 대해 평균)한 것이다.Specifically, 33 patients of each of the Example group and the Comparative Example group were selected and taken 2 capsules (or tablets) once each day, and blood was collected according to a predetermined cycle, and then the Example group and the Comparative Example group were changed, and after 14 days of drug holiday, Two capsules (or tablets) were taken once again on day 15 and blood samples were taken at the same cycle (average for 61 out of the first 66 people, except for 5 dropouts).
도 19는 클로피도그렐의 혈중농도 그래프를, 도 20은 아스피린의 혈중농도 그래프를, 도 21은 아스피린의 대사체인 살리실산의 혈중농도 그래프를 나타낸다.19 is a blood concentration graph of clopidogrel, FIG. 20 is a blood concentration graph of aspirin, and FIG. 21 is a blood concentration graph of salicylic acid, a metabolite of aspirin.
구체적으로, 도 19 내지 도 21의 실험 결과를 다음과 같이 정리할 수 있다.Specifically, the experimental results of FIGS. 19 to 21 may be summarized as follows.
도 19Figure 19
실시예: 본 발명의 복합제제 투여 후 클로로피도그렐의 혈중농도 측정Example: Measurement of blood concentration of chloropidogrel after administration of the combination preparation of the present invention
비교예: 플라빅스정 투여 후 클로로피도그렐의 혈중농도 측정Comparative Example: Measurement of Blood Levels of Chloropidogrel after Plavix Tablet Administration
도 20Figure 20
실시예: 본 발명의 복합제제 투여 후 아스피린의 혈중농도 측정Example: Measurement of blood concentration of aspirin after administration of the combination preparation of the present invention
비교예: 아스트릭스 캡슐 투여 후 아스피린의 혈중농도 측정Comparative Example: Determination of Aspirin Blood Levels after Astrix Capsule Administration
도 21Figure 21
실시예: 본 발명의 복합제제 투여 후 살리실산의 혈중농도 측정Example: Measurement of blood concentration of salicylic acid after administration of the combination preparation of the present invention
비교예: 아스트릭스 캡슐 투여 후 살리실산의 혈중농도 측정Comparative Example: Measurement of Blood Concentration of Salicylic Acid after Astrix Capsule Administration
상기 도 19 내지 도 21은 본 발명의 복합제제가 클로피도그렐 또는 아스피린 단일제제와 거의 유사한 혈중농도 변화를 나타내고 있으며, 따라서 전술한 본 발명의 효과를 완전히 발현함을 보여주고 있다.19 to 21 show that the co-formulation of the present invention shows almost similar changes in blood concentrations as clopidogrel or aspirin mono-formulation, thus fully expressing the effects of the present invention described above.
이상에서는 본 발명의 바람직한 실시예에 대해서 설명하였으나, 본 발명은 상술한 특정의 실시예에 한정되지 아니하며, 당해 기술분야에서 통상의 지식을 가진 자라면 본원 발명의 요지를 벗어남이 없이 다양한 변형 실시가 가능함은 물론이다. 따라서, 본 발명의 범위는 위의 실시예에 국한해서 해석되어서는 안되며, 후술하는 특허청구범위뿐만 아니라 이 특허청구범위와 균등한 것들에 의해 정해져야 할 것이다.In the above description of the preferred embodiment of the present invention, the present invention is not limited to the specific embodiments described above, those skilled in the art various modifications without departing from the gist of the present invention Of course it is possible. Therefore, the scope of the present invention should not be construed as being limited to the above embodiments, but should be determined not only by the claims below but also by the equivalents of the claims.

Claims (17)

  1. (A) 부형제를 포함하는 내핵,(A) an inner core comprising an excipient,
    상기 내핵의 바깥에 인접하고, 약리학적 활성성분으로서 클로피도그렐, 그의 이성질체 또는 그의 약제학적으로 허용가능한 염 및 제 1 결합제를 포함하는 클로피도그렐 외핵, 및Adjacent 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
    상기 외핵의 바깥에 인접하고, 제 2 결합제 및 제 1 가소제를 포함하는 속방보호층Immediate protective layer adjacent to the outside of the outer core, comprising a second binder and a first plasticizer
    을 포함하는 클로피도그렐 과립,Clopidogrel granules, including
    (B) 부형제를 포함하는 내핵,(B) an inner core comprising an excipient,
    상기 내핵의 바깥에 인접하고, 약리학적 활성성분으로서 아스피린 또는 그의 약제학적으로 허용가능한 염 및 제 3 결합제를 포함하는 아스피린 외핵, 및Aspirin external nucleus adjacent to the outside of the inner core and comprising as a pharmacologically active ingredient aspirin or a pharmaceutically acceptable salt thereof and a third binder, and
    상기 외핵의 바깥에 인접하고, 장용성 코팅제 및 제 2 가소제를 포함하는 장용층An enteric layer adjacent to the outside of the outer core and comprising an enteric coating and a second plasticizer
    을 포함하는 아스피린 과립,Aspirin granules, including
    (C) 상기 클로피도그렐 과립 및 아스피린 과립을 수용하는 캡슐(C) a capsule containing the clopidogrel granules and aspirin granules
    을 포함하는 복합제제.Combination formulations comprising a.
  2. 청구항 1에 있어서,The method according to claim 1,
    상기 클로피도그렐 외핵은 제 3 가소제를 추가로 포함하는 것을 특징으로 하는 복합제제.The clopidogrel outer core further comprises a third plasticizer.
  3. 청구항 1에 있어서,The method according to claim 1,
    상기 아스피린 외핵은 제 4 가소제를 추가로 포함하는 것을 특징으로 하는 복합제제.Said aspirin outer core further comprises a fourth plasticizer.
  4. 청구항 1 내지 청구항 3 중 어느 한 청구항에 있어서,The method according to any one of claims 1 to 3,
    상기 부형제는 설탕, 전분 ,미결정셀룰로오스, 락토오스, 카르나우바 왁스, 만니톨, 주석산, 자일리톨 및 그 혼합물로 이루어진 군에서 선택된 것을 특징으로 하는 복합제제.The excipient is a complex, characterized in that selected from the group consisting of sugar, starch, microcrystalline cellulose, lactose, carnauba wax, mannitol, tartaric acid, xylitol and mixtures thereof.
  5. 청구항 1 내지 청구항 3 중 어느 한 청구항에 있어서,The method according to any one of claims 1 to 3,
    상기 클로피도그렐의 약제학적으로 허용가능한 염은 클로피도그렐의 황산수소염, 레지네이트, 캄실산염, 베실산염, 나파디실레이트일수화물염, 염산염 및 그 혼합물로 이루어진 군에서 선택된 것을 특징으로 하는 복합제제.The pharmaceutically acceptable salt of clopidogrel is a combination preparation, characterized in that selected from the group consisting of hydrogen sulfate, resinate, campylate, besylate salt, napadisylate monohydrate salt, hydrochloride salt and mixtures thereof of clopidogrel.
  6. 청구항 1 내지 청구항 3 중 어느 한 청구항에 있어서,The method according to any one of claims 1 to 3,
    상기 제 1 결합제, 제 2 결합제 및 제 3 결합제는 각각 독립적으로 치환 또는 비치환된 알킬셀룰로오스 또는 그의 염, 폴리비닐유도체, 폴리알킬렌글리콜, 폴리메타크릴산 및 그 혼합물로 이루어진 군에서 선택된 것을 특징으로 하는 복합제제.The 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. Compound preparation made with.
  7. 청구항 6에 있어서,The method according to claim 6,
    상기 치환 또는 비치환된 알킬셀룰로오스 또는 그의 염은 메틸셀룰로오스, 에틸셀룰로오스, 히드록시에틸셀룰로오스, 메틸히드록시에틸셀룰로오스, 히드록시프로필셀룰로오스, 히드록시프로필메틸셀룰로오스, 카르복시메틸셀룰로오스나트륨 및 그 혼합물로 이루어진 군에서 선택된 것을 특징으로 하는 복합제제.The substituted or unsubstituted alkyl cellulose or a salt thereof is a group consisting of methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, methyl hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose sodium and mixtures thereof. Combination formulations characterized in that selected from.
  8. 청구항 6에 있어서,The method according to claim 6,
    상기 폴리비닐유도체는 폴리비닐피롤리돈, 폴리비닐알코올 및 그 혼합물로 이루어진 군에서 선택된 것을 특징으로 하는 복합제제.The polyvinyl derivative is a composite preparation, characterized in that selected from the group consisting of polyvinylpyrrolidone, polyvinyl alcohol and mixtures thereof.
  9. 청구항 6에 있어서,The method according to claim 6,
    상기 폴리알킬렌글리콜은 폴리에틸렌글리콜, 폴리프로필렌글리콜 및 그 혼합물로 이루어진 군에서 선택된 것을 특징으로 하는 복합제제.The polyalkylene glycol is a composite preparation, characterized in that selected from the group consisting of polyethylene glycol, polypropylene glycol and mixtures thereof.
  10. 청구항 6에 있어서,The method according to claim 6,
    상기 폴리메타크릴산은 폴리(부틸메타크릴산-co-(2-디메틸아미노에틸)메타크릴산-co-메틸메타크릴산), 폴리(에틸아크릴산-co-메틸메타크릴산), 폴리(에틸아크릴산-co-메틸메타크릴산-co-트리메틸아미노에틸메타크릴산 클로라이드) 및 그 혼합물로 이루어진 군에서 선택된 것을 특징으로 하는 복합제제.The polymethacrylic acid is poly (butyl methacrylate-co- (2-dimethylaminoethyl) methacrylate-co-methylmethacrylic acid), poly (ethylacrylic acid-co-methylmethacrylic acid), poly (ethylacrylic acid) -co-methylmethacrylic acid-co-trimethylaminoethylmethacrylic chloride) and a mixture thereof.
  11. 청구항 1 내지 청구항 3 중 어느 한 청구항에 있어서,The method according to any one of claims 1 to 3,
    상기 제 1 가소제, 제 2 가소제, 제 3 가소제 및 제 4 가소제는 각각 독립적으로 글리콜, 에스테르, 오일, 글리세린, 글리세린유도체 및 그 혼합물로 이루어진 군에서 선택된 것을 특징으로 하는 복합제제.The first plasticizer, the second plasticizer, the third plasticizer and the fourth plasticizer are each independently a combination, characterized in that selected from the group consisting of glycol, ester, oil, glycerin, glycerin derivatives and mixtures thereof.
  12. 청구항 11에 있어서,The method according to claim 11,
    상기 글리콜은 프로필렌글리콜, 폴리에틸렌글리콜 및 그 혼합물로 이루어진 군에서 선택된 것을 특징으로 하는 복합제제.The glycol is a composite preparation, characterized in that selected from the group consisting of propylene glycol, polyethylene glycol and mixtures thereof.
  13. 청구항 11에 있어서,The method according to claim 11,
    상기 에스테르는 프탈산디에틸, 프탈산디부틸, 디부틸세바케이트, 트리에틸시트레이트, 아세틸트리에틸시트레이트, 아세틸트리부틸시트레이트, 트리아세틴 및 그 혼합물로 이루어진 군에서 선택된 것을 특징으로 하는 복합제제.The ester is a combination, characterized in that selected from the group consisting of diethyl phthalate, dibutyl phthalate, dibutyl sebacate, triethyl citrate, acetyl triethyl citrate, acetyl tributyl citrate, triacetin and mixtures thereof.
  14. 청구항 1 내지 청구항 3 중 어느 한 청구항에 있어서,The method according to any one of claims 1 to 3,
    상기 장용성 코팅제는 쉘락, 히드록시프로필메틸셀룰로오스아세테이트숙시네이트, 히드록시프로필메틸셀룰로오스프탈레이트, 셀룰로오스아세테이트프탈레이트, 셀룰로오스아세테이트, 폴리비닐알코올프탈레이트, 폴리(메타크릴산-co-메틸메타크릴산), 폴리(메틸아크릴산-co-메틸메타크릴산-co-메타크릴산), 폴리(메타크릴산-co-에틸아크릴산) 및 그 혼합물로 이루어진 군에서 선택된 것을 특징으로 하는 복합제제.The enteric coating agent is shellac, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, cellulose acetate phthalate, cellulose acetate, polyvinyl alcohol phthalate, poly (methacrylic acid-co-methylmethacrylic acid), poly ( Methylacrylic acid-co-methylmethacrylic acid-co-methacrylic acid), poly (methacrylic acid-co-ethylacrylic acid), and a mixture thereof.
  15. 청구항 1 내지 청구항 3 중 어느 한 청구항에 있어서,The method according to any one of claims 1 to 3,
    상기 클로피도그렐 외핵, 아스피린 외핵, 속방보호층 또는 장용층은 희석제, 활택제, 안정화제, 필름코팅제 및 그 혼합물로 이루어진 군에서 선택된 첨가제를 추가로 포함하는 것을 특징으로 하는 복합제제.The clopidogrel outer core, aspirin outer core, immediate protective layer or enteric layer is a combination, characterized in that further comprising an additive selected from the group consisting of diluents, lubricants, stabilizers, film coating agents and mixtures thereof.
  16. 청구항 1 내지 청구항 3 중 어느 한 청구항에 있어서,The method according to any one of claims 1 to 3,
    상기 클로피도그렐 100 중량부에 대해 아스피린은 10 내지 1000 중량부인 것을 특징으로 하는 복합제제.Aspirin is a composite formulation, characterized in that 10 to 1000 parts by weight based on 100 parts by weight of the clopidogrel.
  17. 청구항 1 내지 청구항 3 중 어느 한 청구항에 있어서,The method according to any one of claims 1 to 3,
    상기 캡슐은 경질 캡슐인 것을 특징으로 하는 복합제제.The capsule is a combination preparation, characterized in that the hard capsule.
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KR101843396B1 (en) 2016-04-04 2018-03-29 가톨릭대학교 산학협력단 Formulation composition of once-daily fixed-dose combination bilayer tablets of cilostazol and clopidogrel and manufacturing 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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