WO2009028900A2 - Oral administration drug comprising clopidogrel besylate - Google Patents

Oral administration drug comprising clopidogrel besylate Download PDF

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Publication number
WO2009028900A2
WO2009028900A2 PCT/KR2008/005079 KR2008005079W WO2009028900A2 WO 2009028900 A2 WO2009028900 A2 WO 2009028900A2 KR 2008005079 W KR2008005079 W KR 2008005079W WO 2009028900 A2 WO2009028900 A2 WO 2009028900A2
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WO
WIPO (PCT)
Prior art keywords
acid
clopidogrel
clopidogrel besylate
pharmaceutical drug
besylate
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PCT/KR2008/005079
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French (fr)
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WO2009028900A3 (en
Inventor
Sung Wuk Kim
Sung Soo Jun
Young Gwan Jo
Ja Seong Koo
Sang Ouk Sun
Jin Hee Yu
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Hanall Pharmaceutical Co., Ltd.
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Publication of WO2009028900A2 publication Critical patent/WO2009028900A2/en
Publication of WO2009028900A3 publication Critical patent/WO2009028900A3/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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • 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
    • 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
    • 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
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1611—Inorganic compounds
    • 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
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
    • 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
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing

Definitions

  • the present invention relates to a pharmaceutical drug for oral administration comprising clopidogrel besylate as an active ingredient with excellent therapeutic effects in the aspects of pharmacokinetics, pharmacodynamics and storage stability without any difficulty in tableting during the manufacturing process by using wet granulation method of adding a binding solution containing a low-grade alcohol, and a method of preparing the same.
  • Clopidogrel generally known as methyl(+)-(S)- ⁇ -(o-chlorophenyl)-6,7- dihydrothieno[3,2-c]pyridine-5(4H)-acetate, has a structure as represented by Formula (1) below.
  • clopidogrel is a drug effective for the prevention and treatment of various platelet-related blood vessel diseases, such as stroke, cerebral arteriosclerosis, myocardial infarction, angina, arrhythmia, peripheral artery atresia and Buerger's disease.
  • Clopidogrel has a specific inhibitory activity against platelet aggregation mediated by adenosine diphosphate(ADP), which is important in thrombus formation.
  • ADP adenosine diphosphate
  • Clopidogrel is orally administrated and metabolized in the liver to become an active metabolite.
  • the active metabolite prevents ADP from binding an ADP receptor by selectively and irreversibly modifying an ADP receptor present in the platelets. Further, the active metabolite inhibits the binding between fibrinogen and GP lib/ Eta complex mediated by ADP and properly controls the amplification of platelet aggregation, induced by ADP. Consequently, through these mechanisms, clopidogrel provides the antiplatelet and antithrombotic effects.
  • Once clopidogrel modifies an ADP receptor irreversibly in the platelet its inhibitory activity against platelet aggregation is continued for 7 days, the lifetime of platelets.
  • clopidogrel represented by Formula (1) is not a solid but a form with a sticky semi-solid property having high viscosity. It is hardly soluble in water and almost impossible to be prepared into a solid formulation. Therefore, its value in the industrial aspect is remarkably low. Further, because the clopidogrel is not fully stable, it is hard to maintain it to have the pharmaceutically required purity of compounds such as an enantiomer, and a related compound.
  • a conventional method to solve this problem is to form pharmaceutically acceptable acid-added salts with an innoxious inorganic or organic acid, but not all inorganic or organic salts are able to solve the above problem.
  • European Pat. No. 281459 discloses a method to prepare a clopidogrel bisulfate to increase stability and solubility of clopidogrel. It is commercially available as PLAVIX (Sanofi-Synthelabo, France) and is being widely used, solving the above drawbacks of clopidogrel has.
  • PLAVIX Sanofi-Synthelabo, France
  • concentrated sulfuric acid is essential for the preparation of clopidogrel bisulfate, and the resultant has a defect of strong acidity due to an azided proton. This acidity negatively affects the interactions with numerous pharmaceutical ingredients and the safety of the drugs manufactured thereof.
  • 2007-33252 disclose the clopidogrel napadisilate and clopidogrel resinate (ion-exchange salts) to improve the disadvantages of clopidogrel. They also disclose that, depending on each salt, stability and preparation efficiency were much improved than clopidogrel bisulfate. However, this result is irrelevant to the stable composition of clopidogrel besylate to be provided in the present invention.
  • Korean Published Pat. No. 2004-101503 relates to a preparation method of benzosulfonic acid (besylate) salt of clopidogrel.
  • clopidogrel besylate has superior stability to bisulfate.
  • clopidogrel besylate mentioned in this patent has a melting point of about 134 ° C, which is much lower than that of clopidogrel bisulfate.
  • glutinous property we could find that there occurs a problem during the long tableting process in the present invention.
  • Korean Published Pat. Nos. 2007-44323, 2007-9851, 2007-34681, and Korean Pat. No. 684099 disclose a stable composition comprising clopidogrel or clopidogrel bisulfate.
  • the preparation methods of the above patents are different from the present invention, which relates to the improvement of the unique physical properties of clopidogrel besylate. That is, known preparation methods of clopidogrel and its salts compositions are not applicable to a pharmaceutical preparation containing clopidogrel besylate.
  • the inventors of the present invention developed a pharmaceutical drug for oral administration comprising clopidogrel besylate as an active ingredient prepared by wet granulation method using a binding solution containing a low-grade alcohol, thereby improving the procedural difficulties caused by the physical properties of clopidogrel besylate in the manufacturing process, while concurrently optimizing pharmacokinetical properties of absorption, distribution, metabolism, excretion in order to maximize the efficacy of clopidogrel, and improving the pharmacodynamical properties of inhibitory activity against the platelet aggregation, and maintaining its stability during the long-term storage.
  • the object of the present invention is to provide a pharmaceutical drug for oral administration comprising clopidogrel besylate as an active ingredient prepared by wet granulation method using a binding solution containing a low-grade alcohol, thereby removing the difficulties in tableting during the manufacturing process, while providing excellent therapeutic effects in the aspects of pharmacokinetics and pharmacodynamics, and superior storage stability, and its preparation method.
  • the present invention aims to develop a pharmaceutical drug for oral administration comprising clopidogrel besylate as an active ingredient, prepared by wet granulation method using a binding solution containing a low-grade alcohol.
  • the present invention also aims to provide a method of preparing the pharmaceutical drug for oral administration containing clopidogrel besylate, which comprising: 1) mixing clopidogrel besylate with a diluent, an absorbent and a binder;
  • step V) 2) adding a binding solution containing a low-grade alcohol into the mixture obtained in step V) 1 followed by kneading, drying and milling to prepare granules;
  • step 2) mixing the granules obtained in step 2) with one or more excipients selected from the group consisting of a disintegrant, a stabilizer, a lubricant and an absorbent; and
  • step 3 tableting and coating the granules obtained in step 3).
  • the pharmaceutical drug containing clopidogrel besylate of the present invention improves the physical properties of clopidogrel besylate during the manufacturing process, thereby eliminating the existing procedural difficulties. Further, as shown in the results of experiments performed to healthy adult subjects, the pharmaceutical drug showed superiorities in pharmacokinetic activities such as absorption, distribution, metabolism, excretion as well as in pharmacodynamic activities such as inhibitory activity against platelet aggregation, which maximizes the effectiveness of clopidogrel.
  • the pharmaceutical composition containing clopidogrel besylate of the present invention can maintain stably in a long-term storage condition, and thus it is expected to be used in the preparation and treatment of various platelet-related diseases.
  • FIG. 1 is a graph showing the result of dissolution test of clopidogrel in a pH 1.2 medium of tablet in Example 1 and Plavix tablet, the reference drug.
  • FIG. 2 is a graph showing the result of dissolution test of clopidogrel in a pH 4.0 medium of tablet in Example 1 and Plavix tablet, the reference drug.
  • FIG. 3 is a graph showing the result of dissolution test of clopidogrel in a pH 6.8 medium of tablet in Example 1 and Plavix tablet, the reference drug.
  • FIG. 4 is a graph showing the result of dissolution test of clopidogrel in a distilled water of tablet in Example 1 and Plavix tablet, the reference drug.
  • FIG. 5 is a graph showing the blood concentration of clopidogrel of tablet in
  • Example 1 Plavix tablet, the reference drug after oral administration.
  • FIG. 6 is a graph showing the blood concentration of clopidogrel inactive metabolite of tablet in Example 1 and Plavix tablet, the reference drug after oral administration.
  • FIG. 7 is a graph showing the platelet aggregation rate of tablet in Example 1 and Plavix tablet, the reference drug after oral administration.
  • the present invention relates to a pharmaceutical drug for oral administration containing clopidogrel besylate prepared by wet granulation method using alcohol.
  • the present invention was completed by effectively using pharmaceutically acceptable excipients to meet the pharmacokinetic and pharmacodynamic properties of clopidogrel. All excipients used in the invention have low moisture content or non-hygroscopic property, and thus it is possible to provide a long-term storage stability.
  • a pharmaceutical drug containing clopidogrel besylate of the present invention can be formulated into various kinds of solid-phase pharmaceutical preparations, particularly in the forms of granules, tablets, and capsules.
  • Pharmacokinetics mentioned in the present invention is a field of pharmacy focusing on quantitative study of the processes, such as absorption, distribution, metabolism, excretion, etc., of drugs administered into body according to time passage.
  • Pharmacodynamics is a field of pharmacology studying the functions of drugs in living organisms.
  • the present invention may be explained in more detail herein below.
  • the inventors of the present invention while performing intensive researches to overcome procedural difficulties in the manufacturing process due to the low melting point of clopidogrel besylate, which is to remedy disadvantages of clopidogrel bisulfate, discovered that the stickiness of clopidogrel besylate can be removed without degradation of products or increase in impurities when manufactured by means of pharmaceutical wet granulation method using a low- grade alcohol as a binding solution.
  • the low-grade alcohol to be used in the present invention is preferably a Ci - C 4 alcohol, such as methanol, ethanol, isopropanol, etc., more preferably ethanol, and, considering the water-sensitiveness of clopidogrel besylate, most preferably anhydrous ethanol.
  • the low-grade alcohol is used preferably in the amount of 0.01-0.5 parts by weight relative to 1 part by weight of clopidogrel besylate. If it is used less than 0.01 parts by weight, it is hard to improve the physical properties of clopidogrel besylate. In contrast, if it is used more than 0.5 parts by weight, it will result in dissolving of clopidogrel besylate. Therefore, the yield is reduced and manufacturing process becomes more difficult.
  • the inventors of the present invention also discovered that the particle size distribution of clopidogrel besylate is associated with the difficulties in tableting step during the manufacturing process and the absorption rate inside the living body.
  • the particle size of clopidogrel besylate is preferably in the range of 5 - 500 /an (Sauter mean diameter, 0[3,2J), more preferably 10 - 300 /m, and most preferably 15 - 200 /an. If the size of the particle is smaller than 5 /m, the manufacturing process becomes difficult and the yield becomes low. In contrast, if the particle size is larger than 500 /m, body absorption becomes low and thus its bioavailability becomes low.
  • the inventors reduced the difficulties occurring in the manufacturing process, produced a pharmaceutical preparation showing a constant dissolution pattern, obtained pharmacokinetical and pharmacodynamical effects, and enabled to maintain stability in a long-term storage condition. Especially, they confirmed that the moisture content and particle size of diluents, a binder, a disintegrant, and a lubricant, added in the preparation, affect the stability of clopidogrel besylate, and accordingly discovered the optimum composition and contents.
  • the object of the present invention is to provide an excellent pharmaceutical preparation having superior storage stability without difficulties during the tableting step, and maintaining a constant dissolution pattern, thereby having superior properties in the aspects of pharmacokinetics and pharmacodynamics when it is administrated orally.
  • the preparation is produced by the following procedure comprising: 1) mixing clopidogrel besylate with a diluent, an absorbent and a binder;
  • step 2) adding a binding solution containing a low-grade alcohol into the mixture obtained in step 1), followed by kneading, drying and milling to prepare granules;
  • step 2) mixing the granules obtained in step 2) with one or more excipients selected from the group consisting of a disintegrant, a stabilizer, a lubricant and an absorbent; and
  • step 3 tableting and coating the granules obtained in step 3).
  • the diluent to be used in the present invention is at least one selected from the group consisting of starch (including potato starch, corn starch, wheat starch, pregelatinized starch), microcrystalline cellulose (including low-hydrous microcrystalline cellulose), lactose (lactose monohydrate, lactose anhydrous, spray- dried lactose), glucose, sorbitol, mannitol, sucrose, alginate, alkaline earth metal salt, clay, polyethylene glycol, dicalcium phosphate, silicon dioxide, etc., or a mixture thereof but is not limited to these.
  • Preferred examples of the diluents are microcrystalline cellulose and polyethylene glycol.
  • microcrystalline cellulose in particular, low-hydrous microcrystalline cellulose (Vivapur 103, JRS) containing a relatively low moisture content with an average particle size of 50 /M is preferred.
  • polyethylene glycol polyethylene glycol 6,000(PEG 6000) is most preferred.
  • the diluent may be used in the amount of 0.1-1.0 parts by weight relative to 1 part by weight of clopidogrel besylate.
  • the binder to be used in the present invention is at least one selected from the group consisting of starch, microcrystalline cellulose, silica, mannitol, lactose, polyethylene glycol, polyvinyl pyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, natural gum, synthetic gum, copovidone, gelatine, but is not limited to these.
  • the binder low-substituted hydroxypropyl cellulose or polyvinyl pyrrolidone are more preferable.
  • the binder may be used in the amount of 0.01-0.2 parts by weight relative to 1 part by weight of clopidogrel besylate.
  • the disintegrant to be used in the present invention may be at least one selected from the group consisting of starch or modified starch such as sodium starch glycolate, corn starch, potato starch, and pregelatinized starch; clays such as bentonite, montmorillonite, and veegum; celluloses such as microcrystalline cellulose, hydroxypropyl cellulose, and carboxymethyl cellulose; algines such as sodium alginate and alginic acid; cross-linked celluloses such as croscarmellose sodium and croscarmellose calcium; gums such as guar gum and xanthan gum; cross-linked polymers such as cross-linked polyvinylpyrrolidone(crospovidone); effervescent preparations ingredients such as sodium bicarbonate and citric acid, or a mixture thereof but are not limited to these.
  • starch or modified starch such as sodium starch glycolate, corn starch, potato starch, and pregelatinized starch
  • clays such as bentonite, mont
  • the above-mentioned disintegrant is cross-linked polyvinyl pyrrolidone or pregelatinized starch.
  • the disintegrant may be used in the amount of 0.05-0.4 parts by weight relative to 1 part by weight of clopidogrel besylate.
  • the lubricant to be used in the present invention is at least one selected from the group consisting of talc, stearic acid, magnesium stearate, calcium stearate, sodium laurylsulfate, hydrogenated vegetable oil, sodium benzoate, sodium stearyl fumarate, glyceryl monostearate and polyethylene glycol.
  • the lubricant may be used in the amount of 0.01-0.2 parts by weight relative to 1 part by weight of clopidogrel besylate.
  • the absorbent to be used in the present invention is at least one selected from the group consisting of hydrated silicon dioxide, light anhydrous silicic acid, colloidal silicon dioxide(Aerosil, Degussa), aluminum magnesium metasilicate, microcrystalline cellulose, lactose, cross-linked polyvinylpyrrolidone.
  • the absorbent may be used in the amount of 0.01-0.4 parts by weight relative to 1 part by weight of clopidogrel besylate.
  • the stabilizer to be used in the present invention is at least one selected from the group consisting of antioxidant such as butylated hydroxy anisole, butylated hydroxy toluene, carotene, retinol, ascorbic acid, tocopherol, tocopherol polyethylene glycol succinic acid, propyl gallate salts thereof; cyclic compounds of sugars such as cyclodextrin, carboxyethyl cyclodextrin, hydroxypropyl cyclodextrin, sulfobutyl ether cyclodextrin; organic acid such as phosphoric acid, lactic acid, acetic acid, citric acid, tartaric acid, succinic acid, maleic acid, fumaric acid, glycolic acid, propionic acid, gluconic acid, glucuronic acid.
  • antioxidant such as butylated hydroxy anisole, butylated hydroxy toluene, carotene, retinol, ascorbic acid,
  • the stabilizer may be used in the amount of 0.005-0.1 parts by weight relative to 1 part by weight of clopidogrel besylate.
  • the present invention may be pharmaceutically prepared by film coating on the surface of tablets.
  • the film coating layer contains a coating agent, a coating pigments or a mixture thereof.
  • the coating agent to be used for the above-mentioned coating layer preferably contains components including polyvinyl alcohol, hydroxypropyl methylcellulose, methylcellulose, ethylcellulose, polyvinyl alcohol-polyethylene glycol copolymer.
  • the film coating material to be used is preferably a mixture of one or more components, such as Opadry (Colorcon).
  • the coating agent is used in the amount of 0.04-0.1 parts by weight relative to 1 part by weight of clopidogrel besylate.
  • the preparation method of the pharmaceutical drug for oral administration containing clopidogrel besylate is as follows.
  • Step for preparation of a mixture Conventionally in wet granulation method, excluding a few exceptions, the active ingredient is mixed with an absorbent, a diluent, a binder, and then added with a solution. The purpose of this procedure is to obtain uniformity of content and particle size distribution after the final mixture.
  • an absorbent is added first in order to remove the sticky properties of the active ingredient.
  • the amount of the absorbent to be used in the procedure is 0.01-0.4 parts by weight relative to 1 part by weight of clopidogrel besylate. If it exceeds 0.4 parts by weight, granulation in the wet granulation process is difficult and the bulk density becomes increased, thereby generating problems in the final tableting step.
  • the diluent is used in the amount of 0.1-1.0 parts by weight relative to 1 part by weight of clopidogrel besylate.
  • the binder is used in the amount of 0.01-0.2 parts by weight relative to 1 part by weight of clopidogrel besylate.
  • Step 2 Step for preparation of granules:
  • the granulating machine widely used in wet granulation is a high shear mixer or a fluid-bed granulator.
  • the mixture produced by step 1) is added with a low-grade alcohol, the same one described above, and more preferably anhydrous ethanol with little humidity, to produce granules.
  • a stabilizer or a binder may be dissolved to perform as a binding solution.
  • the mixture is dried by a hot water circulation dryer or a fluid-bed dryer, and then the mixture is milled in uniform size. Especially, if it is insufficiently dried in drying process, problems 'will occur during the tableting step.
  • Step for preparation of final mixture The final mixture appropriate for dissolution and tableting process is produced in this step by adding at least one excipient selected from the group consisting of a disintegrant, a stabilizer, a lubricant, and an absorbent.
  • Step for preparation of film-coated tablets The final mixture is compressed to produce tablets by tableting machine, and then the tablet is coated with a coating material.
  • the excipient to be used in the present invention is not limited to the above- mentioned excipient, and also the excipient may be allowed to optionally contain a conventional amount.
  • a pharmaceutical drug for oral administration comprising clopidogrel besylate produced by the above-mentioned steps showed superior properties in the aspect of pharmacokinetics and pharmacodynamics with stability maintained during the long-term storage without any difficulties in the manufacturing process, thereby enabling its scale-up production .
  • the present invention is further described with the following Examples, but it is not limited to these. The following Examples are provided as an exemplification for a detailed description of the invention to a reasonable person in the field of the invention.
  • clopidogrel besylate, a diluent, an absorbent, and a binder were weighed and mixed, and then sieved with a sieve (No. 20).
  • the mixture was put into a high-shear mixer machine (Speedmixer, Geumsung Chemical Machinery Co.,Ltd.) or into a fluid bed granulating machine (SFC-mini or SFC-50, Freund), and then added with a low-grade alcohol and mixed.
  • the resultant Upon completion of the mixing, the resultant was put into a fluid bed dryer (SFC- mini or SFC-50, Freund), dried until its moisture content reaches 0.5-3.0 %, and then milled with a milling machine equipped with a sieve (No. 20). Upon completion of the milling process, the resultant was added with a disintegrant, a stabilizer, an absorbent and mixed together for 8 minutes, then added with a lubricant sieved by a sieve (No. 35), and finally mixed for 4 minutes. The final mixture was compressed in a tableting machine with punches of 9 mm in diameter (MRC-30, Sejong Machinery). Upon completion of the tableting, the tablet was film-coated.
  • SFC- mini or SFC-50, Freund milled with a milling machine equipped with a sieve (No. 20).
  • the resultant was added with a disintegrant, a stabilizer, an absorbent and mixed together for 8 minutes, then added with a lubricant sieved
  • clopidogrel besylate, mannitol, low- hydrous microcrystalline cellulose, colloidal silicon dioxide were weighed and mixed, then the mixture was sieved with a sieve (No. 20). The resultant was mixed with stearic acid, which was already sieved with a sieve (No. 35), for about 4 minutes. The final mixture was compressed in a tableting machine with punches of 9 mm in diameter (MRC-30, Sejong Machinery). Upon completion of the tableting, the tablet was film-coated.
  • a mixture was prepared same as in Comparative Example 2, except that stearic acid was replaced with glyceryl behenate and sodium stearyl fumarate, respectively.
  • clopidogrel besylate, low- hydrous microcrystalline cellulose, colloidal silicon dioxide, low-substituted hydroxypropyl cellulose, polyethylene glycol were weighed and mixed, and the mixture was sieved with a sieve (No. 20).
  • the resultant was mixed with stearic acid, which was already sieved with a sieve (No. 35), for about 4 minutes.
  • the final mixture was compressed in a tableting machine with punches of 9 mm in diameter (MRC-30, Sejong Machinery). Upon completion of the tableting, the tablet was film- coated.
  • composition shown in Table I 1 clopidogrel besylate, low- hydrous microcrystalline cellulose, colloidal silicon dioxide, low-substituted hydroxypropyl cellulose, polyethylene glycol were weighed and mixed, and the mixture was sieved with a sieve (No. 20).
  • the resultant was produced in the form of granules by dry granulation (Roller compactor, Choeun Machinery Co., Ltd.) and then followed by the same procedure as in Example 7.
  • Example 1 The final mixed granules prepared in Example 1 were filled into capsules (No. 1) and prepared in the form of capsules accordingly.
  • a control drug was prepared to have the same composition as the commercially available Plavix (Sanofi-Synthelabo), except for using clopidogrel besylate instead of clopidogrel bisulfate.
  • Each tablet of the above drug was prepared to contain clopidogrel besylate (111.86 mg), mannitol (68.0 mg), polyethylene glycol (34.0 mg), low-hydrous microcrystalline cellulose (31.0 mg), low-substituted hydroxypropyl cellulose (12.9 mg), hydrogenated castor oil (3.3 mg), by mixing, tableting, followed by coating.
  • the resultant was added with cross-linked polyvinyl pyrrolidone (13.0 mg) and colloidal silicon dioxide (20.0 mg), and mixed for 8 minutes, then added with stearic acid (9.0 mg), which was already sieved by a sieve (No. 35). The resultant was mixed together for 4 minutes. The final mixture was compressed in a tableting machine (MRC-30, Sejong Machinery) with punches of 9 mm in diameter, followed by film-coating procedure.
  • MRC-30 Sejong Machinery
  • Clopidogrel besylate (111.86 mg), low-hydrous microcrystalline cellulose (114.16 mg), colloidal silicon dioxide (60 mg), low-substituted hydroxypropyl cellulose (28.0 mg), polyethylene glycol (30.0 mg), cross-linked polyvinyl pyrrolidone (13.0 mg) for 15 minutes and sieved with a sieve (No. 20). Then, the resultant was added with stearic acid (18.0 mg), which was already sieved with a sieve (No. 35), and then mixed together for 4 minutes. The final mixture was compressed by using a tableting machine (MRC-30, Sejong Machinery) with punches of 12 mm and the resultant was film coated.
  • MRC-30 Sejong Machinery
  • the sticking is especially important factor among difficulties in tableting because it can cause low quality of the product and weight deviation, thereby products having uniform content may be difficult to be manufactured.
  • Comparative Example 9 in Table 3, the known methods cannot produce pharmaceutical drugs containing clopidogrel besylate. Further, as shown in Comparative Examples 3, 7 and 8, it was confirmed that increasing or modifying the amount of a lubricant or dry granulation process are not suitable for manufacturing a pharmaceutical drug containing clopidogrel besylate. As in Comparative Example 12, a little improvement may be possible by increasing the amount of the diluent as decreasing the content (%) of the active ingredient, but it is still not applicable to mass production.
  • the increase in the amount of the excipient will result in the decrease in the resulting drug's economical value, thereby increasing the total amount of dose while lowering the patients' compliance to the drug.
  • the granules produced by wet granulation using alcohol did not show any problems during long hours of manufacturing process.
  • Test Example 2 Dissolution Profile Test A comparative dissolution test was carried out with a pharmaceutical preparation in Example 1 and Plavix (Sanofi-Synthelabo) in Comparative Example 10, according to Bioequivalence Test Guidance in the Announcement 2005-64 of Korea Food and Drug Administration.
  • Figures 1-4 show the result of the comparative dissolution test. Based on the results of Figures 1-4, Table 4 shows the result according to the similarity factor in Bioequivalence Guidelines. As shown in Table 4, the two pharmaceutical preparations were equivalent in all the dissolution mediums. The time of maximum blood concentration (Tmax) is 1.0 ⁇ 0.5 hours for clopidogrel, therefore the dissolution profile in the most important simulated gastric fluid (pH 1.2) is almost same as shown in Figure 1. Further, as shown in the standard deviation of the dissolution rate in the present invention, each of the tablets hardly exhibited deviation. Therefore, a pharmaceutical drug containing clopidogrel besylate in the present invention is expected to have superior activity of treatment from the uniform dissolution pattern.
  • Tmax time of maximum blood concentration
  • PH 1.2 simulated gastric fluid
  • a bioavailability test was carried out comparing the pharmacokinetical and pharmacodynamical properties with the pharmaceutical preparation in Example 1 and Plavix tablets in Comparative Example 10, and the subjects were 44 healthy adults. Because the half-life of the active metabolites in clopidogrel in vivo is 0.7 + 0.4 hours and it is not possible to figure out their pharmacokinetical properties, so it is analyzed by measuring pharmacokinetical parameter of clopidogrel parent drug (clopidogrel) and the inactive metabolites. Pharmacodynamical properties were evaluated by measuring the inhibition activity against platelet aggregation. Figures 5 and 6 show the mean plasma concentration profile of clopidogrel parent drug and the inactive metabolites.
  • Figure 7 shows a graph representing the activity of inhibiting aggregation ratio as a parameter for pharmacodynamical analysis.
  • the pharmaceutical preparation containing clopidogrel besylate in the present invention was compared to Plavix tablets, which is verified, based on a pharmaceutical preparation containing clopidogrel presently available in the commercial market, its efficiency and safety in the pharmacokinetical and pharmacodynamical aspects, and the two preparations were confirmed as equivalent.
  • Test Example 4 Stability Test
  • the stability test result in the present invention is represented in the following Tables 5, 6 and 7.
  • Table 5 shows stability test result exhibiting the effect of ethanol used in the present invention.
  • Table 6 shows stability test result of Examples in the present invention analyzed in the exposure condition of accelerated test.
  • Table 7 shows stability test result of Examples in the present invention analyzed in the condition of long-term stability test.
  • the pharmaceutical drug containing clopidogrel besylate prepared according to the present invention showed equal or superior stability to that of Plavix, which is available in the market. Further, in Example 4, where a stabilizer is added, the pharmaceutical drug showed superior stability to that of Example 1, where a stabilizer was not added.

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Abstract

The present invention relates to clopidogrel besylate, and more specifically to a pharmaceutical drug for oral administration containing clopidogrel besylate as an active ingredient, which has superior therapeutic effects from the aspects of pharmacokinetics and pharmacodynamics and storage stability while eliminating difficulty in tableting step by wet granulation method adding a binding solution containing a low-grade alcohol during its manufacturing process, and a method of its preparation.

Description

[INVENTION TITLE] ORAL ADMINISTRATION DRUG COMPRISING CLOPIDOGREL BESYLATE
[TECHNICAL FIELD] The present invention relates to a pharmaceutical drug for oral administration comprising clopidogrel besylate as an active ingredient with excellent therapeutic effects in the aspects of pharmacokinetics, pharmacodynamics and storage stability without any difficulty in tableting during the manufacturing process by using wet granulation method of adding a binding solution containing a low-grade alcohol, and a method of preparing the same.
[BACKGROUND ART]
Clopidogrel, generally known as methyl(+)-(S)-α-(o-chlorophenyl)-6,7- dihydrothieno[3,2-c]pyridine-5(4H)-acetate, has a structure as represented by Formula (1) below.
U.S. Pat. No. 4,847,265 teaches that clopidogrel is a drug effective for the prevention and treatment of various platelet-related blood vessel diseases, such as stroke, cerebral arteriosclerosis, myocardial infarction, angina, arrhythmia, peripheral artery atresia and Buerger's disease. (1 )
Figure imgf000002_0001
Clopidogrel has a specific inhibitory activity against platelet aggregation mediated by adenosine diphosphate(ADP), which is important in thrombus formation. Clopidogrel is orally administrated and metabolized in the liver to become an active metabolite. The active metabolite prevents ADP from binding an ADP receptor by selectively and irreversibly modifying an ADP receptor present in the platelets. Further, the active metabolite inhibits the binding between fibrinogen and GP lib/ Eta complex mediated by ADP and properly controls the amplification of platelet aggregation, induced by ADP. Consequently, through these mechanisms, clopidogrel provides the antiplatelet and antithrombotic effects. Once clopidogrel modifies an ADP receptor irreversibly in the platelet, its inhibitory activity against platelet aggregation is continued for 7 days, the lifetime of platelets.
However, clopidogrel represented by Formula (1) is not a solid but a form with a sticky semi-solid property having high viscosity. It is hardly soluble in water and almost impossible to be prepared into a solid formulation. Therefore, its value in the industrial aspect is remarkably low. Further, because the clopidogrel is not fully stable, it is hard to maintain it to have the pharmaceutically required purity of compounds such as an enantiomer, and a related compound. A conventional method to solve this problem is to form pharmaceutically acceptable acid-added salts with an innoxious inorganic or organic acid, but not all inorganic or organic salts are able to solve the above problem.
European Pat. No. 281459 discloses a method to prepare a clopidogrel bisulfate to increase stability and solubility of clopidogrel. It is commercially available as PLAVIX (Sanofi-Synthelabo, France) and is being widely used, solving the above drawbacks of clopidogrel has. However, concentrated sulfuric acid is essential for the preparation of clopidogrel bisulfate, and the resultant has a defect of strong acidity due to an azided proton. This acidity negatively affects the interactions with numerous pharmaceutical ingredients and the safety of the drugs manufactured thereof. Further, Korean Pat. No. 563455 and Korean Published Pat. No. 2007-33252 disclose the clopidogrel napadisilate and clopidogrel resinate (ion-exchange salts) to improve the disadvantages of clopidogrel. They also disclose that, depending on each salt, stability and preparation efficiency were much improved than clopidogrel bisulfate. However, this result is irrelevant to the stable composition of clopidogrel besylate to be provided in the present invention.
Korean Published Pat. No. 2004-101503 relates to a preparation method of benzosulfonic acid (besylate) salt of clopidogrel. According to the above patent, clopidogrel besylate has superior stability to bisulfate. However, clopidogrel besylate mentioned in this patent has a melting point of about 134 °C, which is much lower than that of clopidogrel bisulfate. And due to its glutinous property, we could find that there occurs a problem during the long tableting process in the present invention. Further, considering the difference between clopidogrel besylate and bisulfate in terms of crystallinity and solubility, it is necessary to provide a special preparation method to guarantee bioavailability in the body, but it is not mentioned in the above patent.
Korean Published Pat. Nos. 2007-44323, 2007-9851, 2007-34681, and Korean Pat. No. 684099 disclose a stable composition comprising clopidogrel or clopidogrel bisulfate. However, the preparation methods of the above patents are different from the present invention, which relates to the improvement of the unique physical properties of clopidogrel besylate. That is, known preparation methods of clopidogrel and its salts compositions are not applicable to a pharmaceutical preparation containing clopidogrel besylate.
[DETAILED DESCRIPTION OF INVENTION] [TECHNICAL PROBLEM]
The inventors of the present invention developed a pharmaceutical drug for oral administration comprising clopidogrel besylate as an active ingredient prepared by wet granulation method using a binding solution containing a low-grade alcohol, thereby improving the procedural difficulties caused by the physical properties of clopidogrel besylate in the manufacturing process, while concurrently optimizing pharmacokinetical properties of absorption, distribution, metabolism, excretion in order to maximize the efficacy of clopidogrel, and improving the pharmacodynamical properties of inhibitory activity against the platelet aggregation, and maintaining its stability during the long-term storage.
The object of the present invention is to provide a pharmaceutical drug for oral administration comprising clopidogrel besylate as an active ingredient prepared by wet granulation method using a binding solution containing a low-grade alcohol, thereby removing the difficulties in tableting during the manufacturing process, while providing excellent therapeutic effects in the aspects of pharmacokinetics and pharmacodynamics, and superior storage stability, and its preparation method.
[TECHNICAL SOLUTION] To solve the above problems, the present invention aims to develop a pharmaceutical drug for oral administration comprising clopidogrel besylate as an active ingredient, prepared by wet granulation method using a binding solution containing a low-grade alcohol.
2)
Figure imgf000006_0001
The present invention also aims to provide a method of preparing the pharmaceutical drug for oral administration containing clopidogrel besylate, which comprising: 1) mixing clopidogrel besylate with a diluent, an absorbent and a binder;
2) adding a binding solution containing a low-grade alcohol into the mixture obtained in step V)1 followed by kneading, drying and milling to prepare granules;
3) mixing the granules obtained in step 2) with one or more excipients selected from the group consisting of a disintegrant, a stabilizer, a lubricant and an absorbent; and
4) tableting and coating the granules obtained in step 3).
[ADVANTAGEOUS EFFECTS]
As stated above, the pharmaceutical drug containing clopidogrel besylate of the present invention improves the physical properties of clopidogrel besylate during the manufacturing process, thereby eliminating the existing procedural difficulties. Further, as shown in the results of experiments performed to healthy adult subjects, the pharmaceutical drug showed superiorities in pharmacokinetic activities such as absorption, distribution, metabolism, excretion as well as in pharmacodynamic activities such as inhibitory activity against platelet aggregation, which maximizes the effectiveness of clopidogrel. In addition, as shown in the result of stability test, it was confirmed that the pharmaceutical composition containing clopidogrel besylate of the present invention can maintain stably in a long-term storage condition, and thus it is expected to be used in the preparation and treatment of various platelet-related diseases.
[BRIEF DESCRIPTION OF THE DRAWINGS]
FIG. 1 is a graph showing the result of dissolution test of clopidogrel in a pH 1.2 medium of tablet in Example 1 and Plavix tablet, the reference drug.
FIG. 2 is a graph showing the result of dissolution test of clopidogrel in a pH 4.0 medium of tablet in Example 1 and Plavix tablet, the reference drug.
FIG. 3 is a graph showing the result of dissolution test of clopidogrel in a pH 6.8 medium of tablet in Example 1 and Plavix tablet, the reference drug.
FIG. 4 is a graph showing the result of dissolution test of clopidogrel in a distilled water of tablet in Example 1 and Plavix tablet, the reference drug. FIG. 5 is a graph showing the blood concentration of clopidogrel of tablet in
Example 1 and Plavix tablet, the reference drug after oral administration.
FIG. 6 is a graph showing the blood concentration of clopidogrel inactive metabolite of tablet in Example 1 and Plavix tablet, the reference drug after oral administration. FIG. 7 is a graph showing the platelet aggregation rate of tablet in Example 1 and Plavix tablet, the reference drug after oral administration.
[BEST MODE] The present invention relates to a pharmaceutical drug for oral administration containing clopidogrel besylate prepared by wet granulation method using alcohol.
The present invention was completed by effectively using pharmaceutically acceptable excipients to meet the pharmacokinetic and pharmacodynamic properties of clopidogrel. All excipients used in the invention have low moisture content or non-hygroscopic property, and thus it is possible to provide a long-term storage stability.
Further, a pharmaceutical drug containing clopidogrel besylate of the present invention can be formulated into various kinds of solid-phase pharmaceutical preparations, particularly in the forms of granules, tablets, and capsules.
Pharmacokinetics mentioned in the present invention is a field of pharmacy focusing on quantitative study of the processes, such as absorption, distribution, metabolism, excretion, etc., of drugs administered into body according to time passage. Pharmacodynamics is a field of pharmacology studying the functions of drugs in living organisms.
The present invention may be explained in more detail herein below. The inventors of the present invention, while performing intensive researches to overcome procedural difficulties in the manufacturing process due to the low melting point of clopidogrel besylate, which is to remedy disadvantages of clopidogrel bisulfate, discovered that the stickiness of clopidogrel besylate can be removed without degradation of products or increase in impurities when manufactured by means of pharmaceutical wet granulation method using a low- grade alcohol as a binding solution.
The low-grade alcohol to be used in the present invention is preferably a Ci - C4 alcohol, such as methanol, ethanol, isopropanol, etc., more preferably ethanol, and, considering the water-sensitiveness of clopidogrel besylate, most preferably anhydrous ethanol.
In the present invention, the low-grade alcohol is used preferably in the amount of 0.01-0.5 parts by weight relative to 1 part by weight of clopidogrel besylate. If it is used less than 0.01 parts by weight, it is hard to improve the physical properties of clopidogrel besylate. In contrast, if it is used more than 0.5 parts by weight, it will result in dissolving of clopidogrel besylate. Therefore, the yield is reduced and manufacturing process becomes more difficult.
Further, the inventors of the present invention also discovered that the particle size distribution of clopidogrel besylate is associated with the difficulties in tableting step during the manufacturing process and the absorption rate inside the living body.
They also resolved the difficulties occurring during the manufacturing process by controlling the particle distribution of clopidogrel besylate, and obtained the optimum factors for the drug in the aspects of pharmacokinetics and pharmacodynamics.
The particle size of clopidogrel besylate is preferably in the range of 5 - 500 /an (Sauter mean diameter, 0[3,2J), more preferably 10 - 300 /m, and most preferably 15 - 200 /an. If the size of the particle is smaller than 5 /m, the manufacturing process becomes difficult and the yield becomes low. In contrast, if the particle size is larger than 500 /m, body absorption becomes low and thus its bioavailability becomes low.
Also, in the present invention, through the optimization of the composition of clopidogrel besylate and pharmaceutically acceptable excipients, including a diluents, a binder, a disintegrant, a lubricant, a stabilizer, the inventors reduced the difficulties occurring in the manufacturing process, produced a pharmaceutical preparation showing a constant dissolution pattern, obtained pharmacokinetical and pharmacodynamical effects, and enabled to maintain stability in a long-term storage condition. Especially, they confirmed that the moisture content and particle size of diluents, a binder, a disintegrant, and a lubricant, added in the preparation, affect the stability of clopidogrel besylate, and accordingly discovered the optimum composition and contents.
The object of the present invention is to provide an excellent pharmaceutical preparation having superior storage stability without difficulties during the tableting step, and maintaining a constant dissolution pattern, thereby having superior properties in the aspects of pharmacokinetics and pharmacodynamics when it is administrated orally.
The preparation is produced by the following procedure comprising: 1) mixing clopidogrel besylate with a diluent, an absorbent and a binder;
2) adding a binding solution containing a low-grade alcohol into the mixture obtained in step 1), followed by kneading, drying and milling to prepare granules;
3) mixing the granules obtained in step 2) with one or more excipients selected from the group consisting of a disintegrant, a stabilizer, a lubricant and an absorbent; and
4) tableting and coating the granules obtained in step 3).
The diluent to be used in the present invention is at least one selected from the group consisting of starch (including potato starch, corn starch, wheat starch, pregelatinized starch), microcrystalline cellulose (including low-hydrous microcrystalline cellulose), lactose (lactose monohydrate, lactose anhydrous, spray- dried lactose), glucose, sorbitol, mannitol, sucrose, alginate, alkaline earth metal salt, clay, polyethylene glycol, dicalcium phosphate, silicon dioxide, etc., or a mixture thereof but is not limited to these. Preferred examples of the diluents are microcrystalline cellulose and polyethylene glycol. As for the microcrystalline cellulose, in particular, low-hydrous microcrystalline cellulose (Vivapur 103, JRS) containing a relatively low moisture content with an average particle size of 50 /M is preferred. As for the polyethylene glycol, polyethylene glycol 6,000(PEG 6000) is most preferred. In the present invention, the diluent may be used in the amount of 0.1-1.0 parts by weight relative to 1 part by weight of clopidogrel besylate.
The binder to be used in the present invention is at least one selected from the group consisting of starch, microcrystalline cellulose, silica, mannitol, lactose, polyethylene glycol, polyvinyl pyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, natural gum, synthetic gum, copovidone, gelatine, but is not limited to these. As for the binder, low-substituted hydroxypropyl cellulose or polyvinyl pyrrolidone are more preferable. Also, the binder may be used in the amount of 0.01-0.2 parts by weight relative to 1 part by weight of clopidogrel besylate.
Further, the disintegrant to be used in the present invention may be at least one selected from the group consisting of starch or modified starch such as sodium starch glycolate, corn starch, potato starch, and pregelatinized starch; clays such as bentonite, montmorillonite, and veegum; celluloses such as microcrystalline cellulose, hydroxypropyl cellulose, and carboxymethyl cellulose; algines such as sodium alginate and alginic acid; cross-linked celluloses such as croscarmellose sodium and croscarmellose calcium; gums such as guar gum and xanthan gum; cross-linked polymers such as cross-linked polyvinylpyrrolidone(crospovidone); effervescent preparations ingredients such as sodium bicarbonate and citric acid, or a mixture thereof but are not limited to these. More preferably, the above-mentioned disintegrant is cross-linked polyvinyl pyrrolidone or pregelatinized starch. In the present invention, the disintegrant may be used in the amount of 0.05-0.4 parts by weight relative to 1 part by weight of clopidogrel besylate.
The lubricant to be used in the present invention is at least one selected from the group consisting of talc, stearic acid, magnesium stearate, calcium stearate, sodium laurylsulfate, hydrogenated vegetable oil, sodium benzoate, sodium stearyl fumarate, glyceryl monostearate and polyethylene glycol. In the present invention, the lubricant may be used in the amount of 0.01-0.2 parts by weight relative to 1 part by weight of clopidogrel besylate. The absorbent to be used in the present invention is at least one selected from the group consisting of hydrated silicon dioxide, light anhydrous silicic acid, colloidal silicon dioxide(Aerosil, Degussa), aluminum magnesium metasilicate, microcrystalline cellulose, lactose, cross-linked polyvinylpyrrolidone. In the present invention, the absorbent may be used in the amount of 0.01-0.4 parts by weight relative to 1 part by weight of clopidogrel besylate.
The stabilizer to be used in the present invention is at least one selected from the group consisting of antioxidant such as butylated hydroxy anisole, butylated hydroxy toluene, carotene, retinol, ascorbic acid, tocopherol, tocopherol polyethylene glycol succinic acid, propyl gallate salts thereof; cyclic compounds of sugars such as cyclodextrin, carboxyethyl cyclodextrin, hydroxypropyl cyclodextrin, sulfobutyl ether cyclodextrin; organic acid such as phosphoric acid, lactic acid, acetic acid, citric acid, tartaric acid, succinic acid, maleic acid, fumaric acid, glycolic acid, propionic acid, gluconic acid, glucuronic acid. Further, various pharmaceutically acceptable additives selected from the group consisting of colorants, flavors may be used in the pharmaceutical preparation. In the present invention, the stabilizer may be used in the amount of 0.005-0.1 parts by weight relative to 1 part by weight of clopidogrel besylate.
If desired, the present invention may be pharmaceutically prepared by film coating on the surface of tablets. The film coating layer contains a coating agent, a coating pigments or a mixture thereof.
The coating agent to be used for the above-mentioned coating layer preferably contains components including polyvinyl alcohol, hydroxypropyl methylcellulose, methylcellulose, ethylcellulose, polyvinyl alcohol-polyethylene glycol copolymer. Further, the film coating material to be used is preferably a mixture of one or more components, such as Opadry (Colorcon). In the present invention, the coating agent is used in the amount of 0.04-0.1 parts by weight relative to 1 part by weight of clopidogrel besylate. The preparation method of the pharmaceutical drug for oral administration containing clopidogrel besylate is as follows.
1) Step for preparation of a mixture: Conventionally in wet granulation method, excluding a few exceptions, the active ingredient is mixed with an absorbent, a diluent, a binder, and then added with a solution. The purpose of this procedure is to obtain uniformity of content and particle size distribution after the final mixture.
In the present invention, an absorbent is added first in order to remove the sticky properties of the active ingredient. The amount of the absorbent to be used in the procedure is 0.01-0.4 parts by weight relative to 1 part by weight of clopidogrel besylate. If it exceeds 0.4 parts by weight, granulation in the wet granulation process is difficult and the bulk density becomes increased, thereby generating problems in the final tableting step.
Further, in order to control the stability, compressibility in tableting process and dissolution pattern of the active ingredient, the diluent is used in the amount of 0.1-1.0 parts by weight relative to 1 part by weight of clopidogrel besylate. The binder is used in the amount of 0.01-0.2 parts by weight relative to 1 part by weight of clopidogrel besylate.
2) Step for preparation of granules: The granulating machine widely used in wet granulation is a high shear mixer or a fluid-bed granulator. The mixture produced by step 1) is added with a low-grade alcohol, the same one described above, and more preferably anhydrous ethanol with little humidity, to produce granules. If necessary, a stabilizer or a binder may be dissolved to perform as a binding solution. After kneading, the mixture is dried by a hot water circulation dryer or a fluid-bed dryer, and then the mixture is milled in uniform size. Especially, if it is insufficiently dried in drying process, problems 'will occur during the tableting step. On the contrary, if it is dried too much, the moisture will be reabsorbed thus raising problems during the storage. Therefore, it is most preferable to keep the moisture content at 0.5-3.0 %(w/w). 3) Step for preparation of final mixture: The final mixture appropriate for dissolution and tableting process is produced in this step by adding at least one excipient selected from the group consisting of a disintegrant, a stabilizer, a lubricant, and an absorbent.
4) Step for preparation of film-coated tablets: The final mixture is compressed to produce tablets by tableting machine, and then the tablet is coated with a coating material.
The excipient to be used in the present invention is not limited to the above- mentioned excipient, and also the excipient may be allowed to optionally contain a conventional amount. A pharmaceutical drug for oral administration comprising clopidogrel besylate produced by the above-mentioned steps showed superior properties in the aspect of pharmacokinetics and pharmacodynamics with stability maintained during the long-term storage without any difficulties in the manufacturing process, thereby enabling its scale-up production . The present invention is further described with the following Examples, but it is not limited to these. The following Examples are provided as an exemplification for a detailed description of the invention to a reasonable person in the field of the invention.
EXAMPLES 1-16
According to the composition shown in Tables 1 and 2, clopidogrel besylate, a diluent, an absorbent, and a binder were weighed and mixed, and then sieved with a sieve (No. 20). The mixture was put into a high-shear mixer machine (Speedmixer, Geumsung Chemical Machinery Co.,Ltd.) or into a fluid bed granulating machine (SFC-mini or SFC-50, Freund), and then added with a low-grade alcohol and mixed. Upon completion of the mixing, the resultant was put into a fluid bed dryer (SFC- mini or SFC-50, Freund), dried until its moisture content reaches 0.5-3.0 %, and then milled with a milling machine equipped with a sieve (No. 20). Upon completion of the milling process, the resultant was added with a disintegrant, a stabilizer, an absorbent and mixed together for 8 minutes, then added with a lubricant sieved by a sieve (No. 35), and finally mixed for 4 minutes. The final mixture was compressed in a tableting machine with punches of 9 mm in diameter (MRC-30, Sejong Machinery). Upon completion of the tableting, the tablet was film-coated.
Comparative Examples 1-3
As the composition shown in Tables 2, clopidogrel besylate, mannitol, low- hydrous microcrystalline cellulose, colloidal silicon dioxide were weighed and mixed, then the mixture was sieved with a sieve (No. 20). The resultant was mixed with stearic acid, which was already sieved with a sieve (No. 35), for about 4 minutes. The final mixture was compressed in a tableting machine with punches of 9 mm in diameter (MRC-30, Sejong Machinery). Upon completion of the tableting, the tablet was film-coated.
Comparative Examples 4-5
A mixture was prepared same as in Comparative Example 2, except that stearic acid was replaced with glyceryl behenate and sodium stearyl fumarate, respectively.
Comparative Example 6
According to the composition shown in Table 2, clopidogrel besylate, low- hydrous microcrystalline cellulose, colloidal silicon dioxide, low-substituted hydroxypropyl cellulose, polyethylene glycol were weighed and mixed, and the mixture was sieved with a sieve (No. 20). The resultant was mixed with stearic acid, which was already sieved with a sieve (No. 35), for about 4 minutes. The final mixture was compressed in a tableting machine with punches of 9 mm in diameter (MRC-30, Sejong Machinery). Upon completion of the tableting, the tablet was film- coated.
Comparative Example 7
A compound was prepared same as in Comparative Example 6 except that cross-linked polyvinyl pyrrolidone was added while an equal amount was reduced for the low-hydrous microcrystalline cellulose. Comparative Example 8
According to the composition shown in Table I1 clopidogrel besylate, low- hydrous microcrystalline cellulose, colloidal silicon dioxide, low-substituted hydroxypropyl cellulose, polyethylene glycol were weighed and mixed, and the mixture was sieved with a sieve (No. 20). The resultant was produced in the form of granules by dry granulation (Roller compactor, Choeun Machinery Co., Ltd.) and then followed by the same procedure as in Example 7.
Example 17 : Production of Capsules
The final mixed granules prepared in Example 1 were filled into capsules (No. 1) and prepared in the form of capsules accordingly.
Table 1
Figure imgf000018_0001
Figure imgf000019_0001
Table 2
Figure imgf000020_0001
Figure imgf000021_0001
Comparative Example 9
A control drug was prepared to have the same composition as the commercially available Plavix (Sanofi-Synthelabo), except for using clopidogrel besylate instead of clopidogrel bisulfate. Each tablet of the above drug was prepared to contain clopidogrel besylate (111.86 mg), mannitol (68.0 mg), polyethylene glycol (34.0 mg), low-hydrous microcrystalline cellulose (31.0 mg), low-substituted hydroxypropyl cellulose (12.9 mg), hydrogenated castor oil (3.3 mg), by mixing, tableting, followed by coating.
Comparative Example 10
The commercially available Plavix (Sanofi-Synthelabo) tablets were used as a control drug in Comparative Examples.
Comparative Example 11 Clopidogrel besylate (111.86 mg), low-hydrous microcrystalline cellulose
(57.16 mg), colloidal silicon dioxide(10 mg), low-substituted hydroxypropyl cellulose (14.0 mg), polyethylene glycol (15.0 mg) were weighed and added, mixed with 50% of ethanol (including 50% of purified water), and then mixed together. Upon completion of the kneading, the resultant was put into a fluid bed dryer (SFC-mini, Freund) and dried until it reaches 0.5-3.0% of moisture content, and then milled in a milling machine equipped with a sieve (No. 20). Upon completion of the milling, the resultant was added with cross-linked polyvinyl pyrrolidone (13.0 mg) and colloidal silicon dioxide (20.0 mg), and mixed for 8 minutes, then added with stearic acid (9.0 mg), which was already sieved by a sieve (No. 35). The resultant was mixed together for 4 minutes. The final mixture was compressed in a tableting machine (MRC-30, Sejong Machinery) with punches of 9 mm in diameter, followed by film-coating procedure.
Comparative Example 12
Clopidogrel besylate (111.86 mg), low-hydrous microcrystalline cellulose (114.16 mg), colloidal silicon dioxide (60 mg), low-substituted hydroxypropyl cellulose (28.0 mg), polyethylene glycol (30.0 mg), cross-linked polyvinyl pyrrolidone (13.0 mg) for 15 minutes and sieved with a sieve (No. 20). Then, the resultant was added with stearic acid (18.0 mg), which was already sieved with a sieve (No. 35), and then mixed together for 4 minutes. The final mixture was compressed by using a tableting machine (MRC-30, Sejong Machinery) with punches of 12 mm and the resultant was film coated.
Test Example 1: Confirmation Test of Difficulties in Tableting process (Appearance)
The result of the difficulties in tablets, which are sticking, prepared by tableting, same as in the stated Examples and Comparative Examples, is represented in the following Table 3. The sticking occurs when the adhesion between the surface of the tablets and the inner surface of the machine is stronger than the inner binding capacity of the tablets in the compression molding procedure.
Table 3 Presence of sticking depending on the amount of the manufactured products
Figure imgf000024_0001
The sticking is especially important factor among difficulties in tableting because it can cause low quality of the product and weight deviation, thereby products having uniform content may be difficult to be manufactured.
As shown in Comparative Example 9 in Table 3, the known methods cannot produce pharmaceutical drugs containing clopidogrel besylate. Further, as shown in Comparative Examples 3, 7 and 8, it was confirmed that increasing or modifying the amount of a lubricant or dry granulation process are not suitable for manufacturing a pharmaceutical drug containing clopidogrel besylate. As in Comparative Example 12, a little improvement may be possible by increasing the amount of the diluent as decreasing the content (%) of the active ingredient, but it is still not applicable to mass production.
Also, the increase in the amount of the excipient will result in the decrease in the resulting drug's economical value, thereby increasing the total amount of dose while lowering the patients' compliance to the drug. However, as shown in the results of Examples 1 and 14, the granules produced by wet granulation using alcohol did not show any problems during long hours of manufacturing process.
Test Example 2 : Dissolution Profile Test A comparative dissolution test was carried out with a pharmaceutical preparation in Example 1 and Plavix (Sanofi-Synthelabo) in Comparative Example 10, according to Bioequivalence Test Guidance in the Announcement 2005-64 of Korea Food and Drug Administration.
Figures 1-4 show the result of the comparative dissolution test. Based on the results of Figures 1-4, Table 4 shows the result according to the similarity factor in Bioequivalence Guidelines. As shown in Table 4, the two pharmaceutical preparations were equivalent in all the dissolution mediums. The time of maximum blood concentration (Tmax) is 1.0 ± 0.5 hours for clopidogrel, therefore the dissolution profile in the most important simulated gastric fluid (pH 1.2) is almost same as shown in Figure 1. Further, as shown in the standard deviation of the dissolution rate in the present invention, each of the tablets hardly exhibited deviation. Therefore, a pharmaceutical drug containing clopidogrel besylate in the present invention is expected to have superior activity of treatment from the uniform dissolution pattern.
Table 4 Analysis of bioequivalence according to the analogous properties
Figure imgf000025_0001
Figure imgf000026_0001
Test Example 3 : Pharmacokinetics and Pharmacodynamics Test
A bioavailability test was carried out comparing the pharmacokinetical and pharmacodynamical properties with the pharmaceutical preparation in Example 1 and Plavix tablets in Comparative Example 10, and the subjects were 44 healthy adults. Because the half-life of the active metabolites in clopidogrel in vivo is 0.7 + 0.4 hours and it is not possible to figure out their pharmacokinetical properties, so it is analyzed by measuring pharmacokinetical parameter of clopidogrel parent drug (clopidogrel) and the inactive metabolites. Pharmacodynamical properties were evaluated by measuring the inhibition activity against platelet aggregation. Figures 5 and 6 show the mean plasma concentration profile of clopidogrel parent drug and the inactive metabolites. Figure 7 shows a graph representing the activity of inhibiting aggregation ratio as a parameter for pharmacodynamical analysis. As it is shown in Figures 5, 6 and 7, the pharmaceutical preparation containing clopidogrel besylate in the present invention was compared to Plavix tablets, which is verified, based on a pharmaceutical preparation containing clopidogrel presently available in the commercial market, its efficiency and safety in the pharmacokinetical and pharmacodynamical aspects, and the two preparations were confirmed as equivalent. Test Example 4 : Stability Test
The stability test result in the present invention is represented in the following Tables 5, 6 and 7. First, Table 5 shows stability test result exhibiting the effect of ethanol used in the present invention. Second, Table 6 shows stability test result of Examples in the present invention analyzed in the exposure condition of accelerated test. Third, Table 7 shows stability test result of Examples in the present invention analyzed in the condition of long-term stability test.
Table 5 Stability test performed by using wet granulation
Figure imgf000027_0001
As shown in Table 5, it was confirmed that the wet granulation method using ethanol does not affect the stability of clopidogrel besylate. However, as shown in the result of Comparative Example 11, high moisture content of a binding solution tends to increase the content of related compounds. Table 6 Result of stability test on the exposure condition of accelerated test
Figure imgf000028_0001
Table 7 Result of stability test on the long-term conservation test condition
Figure imgf000028_0002
As shown in Tables 6 and 7, the pharmaceutical drug containing clopidogrel besylate prepared according to the present invention showed equal or superior stability to that of Plavix, which is available in the market. Further, in Example 4, where a stabilizer is added, the pharmaceutical drug showed superior stability to that of Example 1, where a stabilizer was not added.

Claims

[CLAIMS]
1. A pharmaceutical drug for oral administration containing clopidogrel besylate as an active ingredient, prepared by wet granulation using a binding solution containing low-grade alcohol.
2. The pharmaceutical drug according to Claim 1, wherein the low-grade alcohol is a Ci - C4 alcohol.
3. The pharmaceutical drug according to Claim 1, wherein the low-grade alcohol is used in the amount of 0.01-0.5 parts by weight relative to 1 part by weight of clopidogrel besylate.
4. The pharmaceutical drug according to Claim 1, wherein the particle size of the clopidogrel besylate is 5-500 /a (Sauter mean diameter, D [3,2]).
5. The pharmaceutical drug according to Claim 1, wherein the moisture content in the pharmaceutical drug is 0.5-3.0%(w/w).
6. The pharmaceutical drug for oral administration containing clopidogrel besylate in the form of granules, tablets or capsules.
7. A method of preparing the pharmaceutical drug for oral administration containing clopidogrel besylate, which comprises: 1) mixing clopidogrel besylate with an diluent, absorbent and binder;
2) adding a binding solution containing low-grade alcohol into the mixture obtained in step 1), followed by kneading, drying and milling to prepare granules;
3) mixing the granules obtained in step 2) with one or more excipients selected from the group consisting of a disintegrant, a stabilizer, a lubricant and an absorbent; and,
4) tableting the granules obtained in step 3) and coating.
8. The method according to Claim 7, wherein the diluent in step 1) is at least one selected from the group consisting of starch, microcrystalline cellulose, lactose, glucose, sorbitol, mannitol, sucrose, alginate, alkaline earth metal salt, clay, polyethylene glycol, dicalcium phosphate and silicon dioxide.
9. The method according to Claim 7, wherein the absorbent in step 1) and 3) is at least one selected from the group consisting of hydrated silicon dioxide, light anhydrous silicic acid, colloidal silicon dioxide, aluminum magnesium metasilicate, microcrystalline cellulose, lactose and cross-linking polyvinyl pyrrolidone.
10. The method according to Claim 7, wherein the binder in step 1) is at least one selected from the group consisting of starch, microcrystalline cellulose, silica, mannitol, lactose, polyethylene glycol, polyvinyl pyrrolidone, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, natural gum, synthetic gum, copovidone and gelatine.
11. The method according to Claim 7, wherein the disintegrant in step 3) is at least one selected from the group consisting of sodium starch glycolate, corn starch, potato starch, pregelatinized starch, bentonite, montmorillonite, veegum, crystalline cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, sodium alginate, alginate, croscarmellose sodium, croscarmellose calcium, guar gum, xanthan gum, cross-linked polyvinyl pyrrolidone, sodium bicarbonate and citric acid.
12. The method according to claim 7, wherein the stabilizer in step 3) is at least one selected from the group consisting of butylated hydroxy anisole, butylated hydroxy toluene, carotene, retinol, ascorbic acid, tocopherol, tocopherolpolyethylene glycol succinic acid, propyl gallate, cyclodextrin, carboxy ethyl cyclodextrin, hydroxypropyl cyclodextrin, sulfobutyl ether cyclodextrin, phosphoric acid, lactic acid, acetic acid, citric acid, tartaric acid, succinic acid, maleic acid, fumaric acid, glycolic acid, propionic acid, gluconic acid and glucuronic acid.
13. The method according to Claim 7, wherein the lubricant obtained in step 3) is one or more compounds selected from the group consisting of talc, stearic acid, magnesium stearate, calcium stearate, sodium laurylsulfate, hydrogenated vegetable oil, sodium benzoate, sodium stearyl fumarate, glyceryl monostearate and polyethylene glycol.
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